Chemokine receptor antagonists and use thereof

ABSTRACT

A compound represented by general formula (I): 
                         
a salt thereof, a solvate thereof, or a prodrug thereof wherein all symbols are as defined in the specification has an antagonistic activity against CXCR4 and is therefore useful as a preventive and/or therapeutic agent for CXCR4-mediated diseases, for example, inflammatory and immune diseases (for example, rheumatoid arthritis, arthritis, systemic erythematosus, retinopathy, macular degeneration, pulmonary fibrosis, transplanted organ rejection, etc.), allergic diseases, infections (for example, human immunodeficiency virus infection, acquired immunodeficiency syndrome, etc.), psychoneurotic diseases, cerebral diseases, cardiac/vascular disease (for example, arteriosclerosis, myocardial infarction, stenocardia, cerebral infarction, chronic arterial occlusive disease, etc.), metabolic diseases, and cancerous diseases (for example, cancer, cancer metastasis, etc.), a preventive and/or therapeutic agent for cancerous diseases or infections, or an agent for regeneration therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 12/094,100,filed May 16, 2008 (allowed), which is a 371 National Stage Entry ofPCT/JP2006/323015, filed Nov. 17, 2006, which claims benefit of JP2006-049378, filed Feb. 24, 2006, and JP 2005-334937, filed Nov. 18,2005. The entire disclosures of the prior applications are consideredpart of the disclosure of this continuing application and are herebyincorporated by reference.

TECHNICAL FIELD

The present invention relates to compounds having a basic group which isuseful as medicaments, and use thereof.

More specifically, the present invention relates to (1) compoundsrepresented by formula (I):

(wherein all symbols are as defined hereinafter), and salts thereof,N-oxides thereof or solvates thereof or prodrugs thereof, (2) usethereof, and (3) a method for producing the same.

Chemokine is known as a basic protein which has chemotaxis and anactivating effect on endogenous leucocytes and also has strongheparin-binding abilities. It is now considered that chemokine isassociated with not only control of infiltration of specific leucocytesupon inflammatory and immune responses, but also development, homing oflymphocytes under physiological conditions and migration of hemocyteprecursor cells and somatic cells.

Differentiation, proliferation and cell death of blood cells arecontrolled by various cytokines. Inflammation occurs at a local regionin a living body. Differentiation and maturation of lymphocytes, and thelike are carried out at a specific site. More particularly, requiredvarious cells migrate and accumulate in the specific site and a sequenceof inflammatory and immune responses arise. Thus, as well asdifferentiation, proliferation and death of cells, cell migration isalso an essential phenomenon to an immune system.

In the living body, migration of blood cells start with shiftinghemopoiesis that started at AGM (Aorta Gonad Mesonephros) region viafetal liver to permanent hematopoiesis at bone marrow in a developmentcourse. Moreover, precursors of T cells and thymus dendritic cellsmigrate from fetal liver into bone marrow and then into the thymusgland. They differentiate under thymus environment. The T cells aresubjected to clonal selection migrates into secondary lymphoid tissues,where they contribute to immune responses in periphery. Skin Langerhanscells that caught antigen, thereby undergone activation anddifferentiation, migrate to T cell region in a topical lymph node, wherethey activate naive T cells therein as dendritic cells. The memory Tcells again perform its homing into the lymph node via lymphatic andblood vessels. In addition, B cells, T cells in intestinal epithelia,γδT cells, NKT cells, and dendritic cells migrate from bone marrow notvia thymus, differentiate and contribute to immune responses.

Chemokine is very involved in these various cell migrations. Forexample, SDF-1 (Stromal cell derived factor-1) and its receptor, CXCR4also act on various immune and inflammatory reactions. For example, theyhave been reported to be associated with accumulation and activation ofCD4+T cells in a synovial membrane from a human patient suffering fromrheumatoid arthritis (J. Immunol., 165, 6590-6598 (2000)). In addition,in a CIA model mouse, CXCR4 inhibitor inhibited accumulation ofleucocytes in a joint and dramatically reduced arthritis score (J.Immunol., 167, 4648-4692 (2001)). In a mouse OVA-induced airwayhypersensitive model, an anti-CXCR4 antibody reduced the number ofeosinophiles accumulating in pulmonary interstitial tissues andprevented airway hypersensitivity (J. Immunol., 165, 499-508 (2000)). Inmouse retinopathy model, an anti-SDF-1 antibody inhibits the invasion ofvascular endothelial precursor cell to retina and retinalneoangiogenesis (J. Cli. I, 115, 86-93 (2005)).

There has been reported that SDF-1 and its receptor, CXCR4 play animportant role in maintaining hemopoietic stem cells in bone marrow J.Exp. Med., 185, 111-120 (1997), Blood, 97, 3354-3360 (2001)).Accordingly, control of SDF-1 and CXCR4 is expected to modulaterecruitment of hemopoietic stem cells to peripheral blood and is usefulfor peripheral blood stem cell transplantation and reproductiontransplantation treatment.

SDF-1 and CXCR4 are associated with infiltration of various cancer cellssuch as breast cancer, prostate cancer, and ovarian cancer (Nature, 410,50-56 (2001), Cancer Res., 62, 1832-1837 (2002), Cancer Res., 62,5930-5938 (2002)). In a model of a SCID mouse which is transferred ahuman breast cancer cell strain into, an anti-CXCR4 antibody preventedmetastasis of breast cancer cells to lung (Nature, 410, 50-56 (2001)).Furthermore, an anti-SDF-1 antibody inhibited neoangiogenesis aroundcancer and thereby inhibited cancer cell proliferation (Cell, 121,335-348 (2005)). In human ovarian epithelial tumor, highly expression ofSDF-1 promotes accumulation of plasmacytoid dendritic cells and inhibitsthe act of bone marrow dendritic cells associated with tumor immune andsuppresses tumor immune (Nat. Med., 12, 1339 (2001)). Moreover, SDF-1 isassociated with proliferation and migration of non-Hodgkin's lymphomacells, and in a model of a NOD/SCID mouse which is transferred a humannon-Hodgkin's lymphoma cells into, an anti-CXCR4 antibody inhibitedproliferation of the tumor cells and improved mouse mortality (CancerRes., 62, 3106-3112 (2002)). Furthermore, a low molecular CXCR4antagonist increases apoptosis of intracranially transplantedamedulloblastoma in mice and decrease tumor growth (Proc. Nat. Acad.Sci. USA, 100, 13513-13518 (2003)). And it enhances the effect of animmunostimulant and an anticancer in the model of pulmonary metastasismodel with malignant melanoma (Mol Cancer Ther., 5, 2592-9 (2006)).

SDF-1 and CXCR4 play an important role for formation of hippocampusdentate gyrus granulocyte, that is essential for memory and learning andare associated with development of a disease associated with adultplasticity and pathology of hippocampus, for example Alzheimer'sdisease, stroke and epilepsy (Development, 129, 4249-4260 (2002), Trendsin Neuroscience, 25, 548-549 (2002)).

SDF-1 and CXCR4 are essential for a function of self-reactive B cellsassociated with development of diabetes. In NOD mouse, an anti-SDF-1antibody reduced blood glucose level and the number of mature IgM+Bcells in a periphery tissue (Immunology, 107, 222-232 (2002)). In ahuman arteriosclerotic plaque, SDF-1 was highly expressed and activatedblood platelets (Circ. Res., 86, 131-138 (2000)).

SDF-1 and CXCR4 are involved in residence of hemopoietic stem cells andhemopoietic precursor cells in bone marrow. CXCR4 antagonist, AMD 3100in combination with G-CSF increased the numbers of hemopoietic stemcells and hemopoietic precursor cells in periphery blood (JournalExperimental Medicine, 2001, 1307-1318 (2005)). In addition, it is knownthat administrating a low molecular CXCR4 antagonist to human increasesneutrophilic leukocytes, lymphocytes, monocytes and the like increase inperipheral blood (Blood, 102, 2728-2730 (2003)). Therefore, a lowmolecular CXCR4 antagonist is expected to have an immunoenhancingeffect.

In addition, the results of SDF-1/CXCR4 knock-out mice showed that SDF-1is essential for functions of central nervous system, heart and vesselsof gastrointestinal tract in addition to lymphocytes (Nature, 382,635-639 (1996), Nature, 393, 591-594 (1998), Nature, 393, 595-599(1998)). Accordingly, it may be associated with a disease of thesetissues.

Thus, chemokine receptors are expressed at various specific cells and ata specific time. They are largely associated with the control ofinflammatory- and immune responses through a mechanism by which theireffector cells accumulate in a site where chemokine is produced.

Acquired immunodeficiency syndrome (also called AIDS) that caused byinfection of human immunodeficiency virus (hereinafter abbreviated toHIV) is one of diseases for which therapies are the most eagerly desiredlately. Once HIV infection has been established in a main target cell,CD4+ cell, HIV repetitively proliferates in a patient's body and after awhile severely destroys T cells responsible for immunological functionsby necrosis. In this process, immunological functions are graduallydeteriorated, various immunocompromised states become to develop such asfever, diarrhea and swelling of a lymph node, and various opportunisticinfections such as carinii pneumonia are easily complicated. It is wellknown that such a state is the onset of AIDS and induces malignanttumors such as Kaposi's sarcoma and becomes severe.

Currently, various preventive and therapeutic treatments for AIDS aretried as follows: for example, (1) inhibition of HIV proliferation byadministration of reverse transcriptase inhibitors and proteaseinhibitors, and (2) prevention or alleviation of opportunisticinfections by administration of an immunostimulant, etc.

HIV mainly infects helper T cells which play a key role in the immunesystem. Since 1985, it has been known that in this process HIV utilizesa membrane protein CD4 that is expressed on the membrane of T cells(Cell, 52, 631 (1985)). CD4 molecule consists of 433 amino acid residuesand is expressed in macrophages, some of B cells, vascular endothelialcells, Langerhans cells in skin tissues, dendritic cells located inlymphatic tissues, glia cells of central nervous system and the like inaddition to mature helper T cells. However, as it becomes obvious thatHIV infection cannot be established with only CD4 molecule, the possiblepresence of some factor that is responsible for infection of cell withHIV, other than CD4 molecule, has been suggested.

In 1996, a cell membrane protein called Fusin has been identified as afactor responsible for HIV infection other than a CD4 molecule (Science,272, 872 (1996)). This Fusin molecule has been demonstrated to be areceptor for SDF-1, namely, CXCR4. In addition, it has been shown thatSDF-1 specifically inhibits infection of T cell-directed (X4) HIV invitro (Nature, 382, 829 (1996), Nature, 382, 833 (1996)). This may beconsidered that SDF-1 binds to CXCR4 prior to HIV, thereby taking away ascaffold for infecting a cell from HIV resulting in inhibition of HIVinfection.

Also, at the same period, there has been found that another chemokinereceptor CCR5, that is a receptor for RANTES, MIP-1α, and MIP-1β, isutilized at infection of macrophage-directed (R5) HIV (Science, 272,1955 (1996)).

Accordingly, those which can compete with HIV for CXCR4 and CCR5 orthose which bind to a HIV virus and prevent for said virus from bindingto CXCR4 and CCR5 may be a HIV infection inhibitor. In addition, thereis a case where a low molecular weight compound discovered as a HIVinfection inhibitor was showed to be indeed an antagonist of CXCR4(Nature Medicine, 4, 72 (1998)).

As described above, compounds having an antagonistic activity againstCXCR4 is effective, such as, for prevention and/or treatment ofinflammatory and immune diseases, allergic diseases, infections,particularly HIV infection, and diseases associated with the infection,psychoneurotic diseases, cerebral diseases, cardiovascular diseases,metabolic diseases, cancerous diseases and the like. Also, the compoundsare useful for cell medical treatment and regeneration therapy.

Heretofore, some compounds having an antagonistic activity against CXCR4have been reported. For example, it is disclosed that a compoundrepresented by formula (X):

(wherein A^(X) represents

A^(1X) and A^(2X) each independently represents a hydrogen atom, anoptionally substituted monocyclic or polycyclic heteroaromatic ring, oran optionally substituted monocyclic or polycyclic aromatic ring; G^(1X)represents a single bond or —CR^(2X)R^(3X)—; R^(1X), R^(2X), and R^(3X)represent an optionally substituted alkyl group having 1 to 6 carbonatom(s), etc.; W^(X) represents an optionally substituted alkylene grouphaving 1 to 7 carbon atom(s), an optionally substituted monocyclic orpolycyclic heteroaromatic ring, an optionally substituted monocyclic orpolycyclic aromatic ring, etc.; X^(X) represents -z^(1X)-CO-z^(2X)-;z^(1X) and z^(2X) each independently represents a single bond, NR^(13X),etc.; y^(X) represents —CO—; D^(1X) and D^(2X) each independentlyrepresents a hydrogen atom or -G^(2X)-R^(4X); G^(2X) represents anoptionally substituted alkylene group having 1 to 15 carbon atom(s),etc.; R^(4X) represents a hydrogen atom, an optionally substitutedmonocyclic or polycyclic heteroaromatic ring, or an optionallysubstituted monocyclic or polycyclic aromatic ring; n2X represents 0 to4; n1X represents 0 to 3; and B^(X) represents —NR^(6X)R^(7X), and onlyrequired portions were extracted with respect to definition of eachgroup), or a pharmaceutically acceptable salt has an antagonisticactivity against CXCR4 (see WO2003/029218 pamphlet).

Also, it is disclosed that a compound represented by formula (Y):

(wherein n1Y, n2Y and n3Y represent 0 to 3; R^(1Y), R^(2Y), R^(3Y),R^(4Y), R^(5Y) and R^(6Y) each independently represents a hydrogen atom,or an optionally substituted alkyl group having 1 to 15 carbon atom(s),etc.; A^(1Y) and A^(2Y) each independently represents an optionallysubstituted monocyclic or polycyclic heteroaromatic ring, etc.; W^(Y)represents an optionally substituted alkylene group having 1 to 15carbon atom(s), etc.; X^(Y) represents O, CH₂, NR^(11Y), etc.; D^(Y)represents -Q^(Y)-Y^(Y)—B^(Y); Q^(Y) represents a single bond or —CO—when X^(Y) is NR^(11Y), etc.; Y^(Y) represents—(CR^(18Y)R^(19Y))_(m3Y)-, etc.; R^(18Y) and R^(19Y) each independentlyrepresents a hydrogen atom, or an optionally substituted alkyl grouphaving 1 to 15 carbon atom(s), etc.; m3Y represents 0 to 6, etc.; B^(Y)represents —NR^(25Y)R^(26Y); and R^(25Y) and R^(26Y) represent ahydrogen atom, an optionally substituted alkyl group having 1 to 15carbon atom(s) when X^(Y) is not CH₂, etc., and only required portionswere extracted with respect to definition of each group), or apharmaceutically acceptable salt or a prodrug thereof has anantagonistic activity against CXCR4 (see WO2004/024697 pamphlet).

Furthermore, it is disclosed that a compound represented by generalformula (Z):

(wherein n1Z, n2Z and n3Z represent 0 to 3; R^(1Z), R^(2Z), R^(3Z),R^(4Z), R^(5Z) and R^(6Z) each independently represents a hydrogen atom,an optionally substituted alkyl group having 1 to 15 carbon atom(s),etc., and R^(5Z) and R^(6Z) may form a carbonyl group together with acarbon atom; A^(1Z) and A^(2Z) each independently represents anoptionally substituted monocyclic or polycyclic heteroaromatic ring,etc.; W^(Z) represents an optionally substituted benzene ring, etc.;X^(Z) represents O, CH₂, or NR^(11Z), etc.; D^(Z) represents-Q^(Z)-Y^(Z)—B^(Z)-; Q_(Z) represents a single bond, —CO—, —CONH—,NR^(12Z), etc. when X^(Z) is CH₂; Y^(Z) represents—(CR^(18Z)R^(19Z))_(m3Z)—, etc.; R^(18Z) and R^(19Z) each independentlyrepresents a hydrogen atom, or an optionally substituted alkyl grouphaving 1 to 15 carbon atom(s), etc.; m3Z represents 0 to 6; B^(Z)represents —NR^(25Z)R^(26Z); and R^(25Z) and R^(26Z) represent ahydrogen atom, or an optionally substituted alkyl group having 1 to 15carbon atom(s), etc. when X^(Z) is not CH₂, and only required portionswere extracted with respect to definition of each group), or apharmaceutically acceptable salt or a prodrug thereof has anantagonistic activity against CXCR4 (see WO2005/085209 pamphlet).

-   Patent Literature 1 WO2003/029218 pamphlet-   Patent Literature 2 WO2004/024697 pamphlet-   Patent Literature 3 WO2005/085209 pamphlet

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

It is earnestly desired to develop an antagonist of CXCR4, which isuseful as a preventive and/or therapeutic agent for inflammatory andimmune diseases (for example, rheumatoid arthritis, arthritis, systemicerythematosus, retinopathy, macular degeneration, pulmonary fibrosis,rejection of transplanted organ, etc.), allergic diseases, infections(for example, human immunodeficiency virus infection, acquiredimmunodeficiency syndrome, etc.), cancerous diseases (for example,cancer, cancer metastasis, etc.), cardiac/vascular diseases (forexample, arteriosclerosis, myocardial infarction, stenocardia, cerebralinfarction, chronic arterial occlusive disease, etc.), or an agent forregeneration therapy, and is also safe with less side effects.

The present invention relates to

[1] A compound represented by formula (I):

wherein A¹ and A² each independently represents a group having a basicgroup;

B¹ and B² each independently represents a bond or a spacer having a mainchain of 1 to 4 atom(s);

E represents a spacer having a main chain of 1 to 10 atom(s);

L represents a bond or a spacer having a main chain of 1 to 4 atom(s);

J represents (1) an aliphatic hydrocarbon group which is substitutedwith a group having a basic group, and also may have a substituent(s),(2) a monocyclic or condensed cyclic group which is substituted with agroup having a basic group, and also may have a substituent(s), (3) aspiro-bound cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s), or (4) a bridged cyclicgroup which may be substituted with a group having a basic group, andalso may have a substituent(s);

G represents a bond, a carbon atom which may have a substituent(s), anoxygen atom, a nitrogen atom which may have a substituent(s), anoptionally oxidized sulfur atom, or -carbon atom which may have asubstituent(s)-nitrogen atom which may have a substituent(s)-;

wherein when J represents (1) or (2), G represents a bond, a carbonylgroup, an oxygen atom, a nitrogen atom which may have a substituent(s)or an optionally oxidized sulfur atom, or B¹ represents a spacer havinga main chain of 1 to 4 atom(s) composed of 1 to 4 group(s) selectedoptionally from —O—, —S—, —CO—, —SO—, —SO₂— and a divalent nitrogen atomwhich may have a substituent(s),

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[2] The compound according to the above [1], wherein A¹ and A² eachindependently represents a nitrogen-containing heterocyclic ring whichmay have a substituent(s), a salt thereof, or an N-oxide thereof, or asolvate thereof, or a prodrug thereof;

[3] The compound according to the above [2], wherein thenitrogen-containing heterocyclic ring is an imidazole ring, abenzimidazole ring, or a pyridine ring, a salt thereof, or an N-oxidethereof, or a solvate thereof, or a prodrug thereof;

[4] The compound according to the above [1], wherein the spacers havinga main chain of 1 to 4 atom(s) represented by B¹ and B² eachindependently represents —CO—, —SO₂—, or —CH₂—, a salt thereof, or anN-oxide thereof, or a solvate thereof, or a prodrug thereof;[5] The compound according to the above [1], wherein G is —CO—, —SO₂—,or —CH₂—, a salt thereof, or an N-oxide thereof, or a solvate thereof,or a prodrug thereof;[6] The compound according to the above [1], wherein E is a divalent 3-to 8-membered monocyclic cyclic group which may have a substituent(s) ora divalent 9- to 10-membered condensed cyclic group which may have asubstituent(s), a salt thereof, or an N-oxide thereof, or a solvatethereof, or a prodrug thereof;[7] The compound according to the above [6], wherein the 3- to8-membered monocyclic cyclic ring is a benzene ring, a salt thereof, oran N-oxide thereof, or a solvate thereof, or a prodrug thereof;[8] The compound according to the above [1], wherein L is —CH₂—, —CO—,—CONH—, or —CH₂—NH— wherein a nitrogen atom is bonded to J in —CONH— and—CH₂—NH—, a salt thereof, or an N-oxide thereof, or a solvate thereof,or a prodrug thereof;[9] The compound according to the above [1], which is2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decan-3-one,2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decan-1-one,or2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-(1-ethylpropyl)-2,9-diazaspiro[5.5]undecan-1-one,a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;[10] The compound according to the above [1], wherein formula (I) isformula (I-1):

wherein ring A^(1A) and ring A^(2A) each independently represents anitrogen-containing heterocyclic ring which may have a substituent(s),

ring E¹ represents a divalent 3- to 8-membered monocyclic cyclic groupwhich may have a substituent(s) or a divalent 9- to 10-memberedcondensed cyclic group which may have a substituent(s), and

other symbols are as defined in the above [1],

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[11] The compound according to the above [1], wherein formula (I) isformula (I-2):

wherein G¹ represents —CO—, —SO₂—, or —CH₂—, other symbols are asdefined in the above [1] or the above [10], a salt thereof, or anN-oxide thereof, or a solvate thereof, or a prodrug thereof;[12] The compound according to the above [11], wherein G¹ is —SO₂—, asalt thereof, or an N-oxide thereof, or a solvate thereof, or a prodrugthereof;[13] The compound according to the above [1], wherein formula (I) isformula (I-3):

wherein B^(1A) and B^(2A) each independently represents —CO—, —SO₂—, or—CH₂—, and other symbols are as defined in the above [1] or the above[10], a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;[14] The compound according to the above [11], wherein

in the group, L^(A) represents (a)-an aliphatic hydrocarbon group having1 to 3 carbon atom(s) which may have a substituent(s)-a nitrogen atomwhich may have a substituent(s)-, or (b) a divalent aliphatichydrocarbon group having 1 to 4 carbon atom(s) which may have asubstituent(s),

when L^(A) represents (a)-an aliphatic hydrocarbon group having 1 to 3carbon atom(s) which may have a substituent(s)-a nitrogen atom which mayhave a substituent(s)-, ring J¹ represents (i) a C3-10 monocyclic orbicyclic carbocyclic ring, or (ii) a 3- to 10-membered monocyclic orbicyclic heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s),

when L^(A) is (b) a divalent aliphatic hydrocarbon group having 1 to 4carbon atom(s) which may have a substituent(s), ring J¹ represents a 3-to 10-membered monocyclic or bicyclic heterocyclic ring which has atleast one nitrogen atom, and also may have an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s),

ring J² represents (i) a C3-10 monocyclic or bicyclic carbocyclic ringwhich is substituted with a group having a basic group, (ii) a 3- to10-membered monocyclic or bicyclic heterocyclic ring composed of acarbon atom(s), an oxygen atom(s) and/or an optionally oxidized sulfuratom(s), which is substituted with a group having a basic group, or(iii) a 3- to 10-membered monocyclic or bicyclic heterocyclic ring whichhas at least one nitrogen atom and also may have an oxygen atom(s)and/or an optionally oxidized sulfur atom(s), and which may besubstituted with a group having a basic group,

ring J¹ and ring J² may have 1 to 8 substituent(s) on the substitutableposition, and when two or more substituents are present, pluralsubstituents may be the same or different, wherein a nitrogen atom whichmay have a substituent(s) in L^(A1) is bonded to ring J^(1a),

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[15] The compound according to the above [14], wherein L^(A) is —CO— or—CH₂—, a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[16] The compound according to the above [14], wherein

wherein L^(A) may be bonded to a nitrogen atom of —NH—, and the nitrogenatom of —NH— may have a substituent(s), a salt thereof, or an N-oxidethereof, or a solvate thereof, or a prodrug thereof;[17] The compound according to the above [14], wherein

wherein L^(A) may be bonded to a nitrogen atom of —NH—, and the nitrogenatom of —NH— may have a substituent(s), a salt thereof, or an N-oxidethereof, or a solvate thereof, or a prodrug thereof;[18] The compound according to the above [11], wherein formula (I) isformula (I-2-a):

wherein ring A^(1B) and ring A^(2B) represent an imidazole ring whichmay have a substituent(s), a benzimidazole ring which may have asubstituent(s), or a pyridine ring which may have a substituent(s),

R^(E) represents a halogen atom or an aliphatic hydrocarbon group, mrepresents an integer of 0 or 1 to 2,

L^(1B) represents —CO— or —CH₂—,

n1 represents an integer of 1 to 2 and, when n1 is 2, two L^(1B)(s) maybe the same or different, and

J^(B) represents:

in the group, the arrow is bonded with L^(1B), and

R¹ represents a hydrogen atom or a substituent, formula (I-2-b):

wherein all symbols are as defined above, or formula (I-2-c):

wherein ring E⁴ represents a pyrrolidine ring which may be substitutedby an aliphatic hydrocarbon group, or a piperidine ring which may besubstituted by an aliphatic hydrocarbon group, and other symbols are asdefined above,

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[19] The compound according to the above [18], wherein the substituentof ring A^(1B) and ring A^(2B) is absent or a C1-8 alkyl group, a saltthereof, or an N-oxide thereof, or a solvate thereof, or a prodrugthereof;

[20] The compound according to the above [18], wherein R¹ is a C4-7monocyclic carbocyclic ring or a C1-8 alkyl group, a salt thereof, or anN-oxide thereof, or a solvate thereof, or a prodrug thereof;

[21] The compound according to the above [10], [11] or [13], wherein

in the group, L^(A) is as defined in the above [14],

(a) when L^(A) is -an aliphatic hydrocarbon group having 1 to 3 carbonatom(s) which may have a substituent(s)-a nitrogen atom which may have asubstituent(s)-, ring J³ represents (i) a bridged carbocyclic ringsubstituted with a group having a basic group, or (ii) a bridgedheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), which is substituted with a grouphaving a basic group,

(b) when L^(A) is a divalent aliphatic hydrocarbon group having 1 to 4carbon atom(s) which may have a substituent(s), ring J³ represents abridged heterocyclic ring which has at least one nitrogen atom which maybe substituted with a group having a basic group, and also may have anoxygen atom(s) and/or an optionally oxidized sulfur atom(s), and

ring J³ may have 1 to 8 substituent(s) on the substitutable position,and when two or more substituents are present, plural substituents maybe the same or different, wherein a nitrogen atom which may have asubstituent(s) in L^(A) is bonded to ring J^(1a),

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[22] The compound according to the above [21], wherein the bridgedcarbocyclic ring is:

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;[23] The compound according to the above [21], wherein the bridgedheterocyclic ring which has at least one nitrogen atom, and also mayhave an oxygen atom(s) and/or an optionally oxidized sulfur atom(s) is:

in the group, a nitrogen atom of —NH— may have a substituent(s), a saltthereof, or an N-oxide thereof, or a solvate thereof, or a prodrugthereof;[24] The compound according to the above [10], [11] or [13], wherein

in the group, L^(A) is as defined in the above [14],

(a) when L^(A) is -(an aliphatic hydrocarbon group having 1 to 3 carbonatom(s) which may have a substituent(s))-(a nitrogen atom which may havea substituent(s))-, ring J⁴ represents (i) a C3-15 monocyclic orcondensed carbocyclic ring substituted with a group having a basicgroup, or (ii) a 3- to 15-membered monocyclic or condensed heterocyclicring composed of a carbon atom(s), an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s), which is substituted with a grouphaving a basic group,

(b) when L^(A) is a divalent aliphatic hydrocarbon group having 1 to 4carbon atom(s) which may have a substituent(s), ring J⁴ represents (iii)a 3- to 15-membered monocyclic or condensed heterocyclic ring which hasat least one nitrogen atom which may be substituted with a group havinga basic group, and also may have an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s), and

ring J⁴ may have 1 to 8 substituent(s) on the substitutable position,and when two or more substituents are present, plural substituents maybe the same or different, wherein a nitrogen atom which may have asubstituent(s) in L^(A) is bonded to ring J⁴,

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[25] The compound according to the above [24], wherein the C3-15monocyclic or condensed carbocyclic ring is:

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;[26] The compound according to the above [25], wherein the C3-15monocyclic or condensed carbocyclic ring is a cyclohexyl group, a saltthereof, or an N-oxide thereof, or a solvate thereof, or a prodrugthereof;[27] The compound according to the above [1], wherein formula (I) isformula (I-4)

wherein ring A^(1B) and ring A^(2B) are as defined in the above [18],

B^(1A) and B^(2A) are as defined in the above [13],

ring E¹ is as defined in the above [13],

L^(A) is as defined in the above [14],

J⁵ represents a spiro-bound cyclic group which may be substituted with agroup having a basic group, and also may have a substituent(s) or abridged cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s), wherein a nitrogen atomwhich may have a substituent(s) in L^(A) is bonded to J⁵,

a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;

[28] The compound according to the above [27], wherein -L^(A)-J⁵ is

in the group, L^(A2) represents a divalent aliphatic hydrocarbon grouphaving 1 to 4 carbon atom(s) which may have a substituent(s), R¹ is asdefined in the above [18], a salt thereof, or an N-oxide thereof, or asolvate thereof, or a prodrug thereof;[29] The compound according to the above [28], wherein R¹ is a cyclicgroup which may have a substituent(s) or an aliphatic hydrocarbon groupsubstituted with a cyclic group which may have a substituent(s), a saltthereof, or an N-oxide thereof, or a solvate thereof, or a prodrugthereof;[30] The compound according to the above [27], wherein ring E¹ is adivalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s), a salt thereof, or an N-oxide thereof, or a solvatethereof, or a prodrug thereof;[31] The compound according to the above [1], wherein formula (I) isformula (I-4-a):

wherein n2 represents an integer of 2 to 4, and plural L^(1B)(s) may bethe same or different, and other symbols are as defined in the above[18], a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof;[32] The compound according to the above [31], wherein the substituentof ring A^(1B) and ring A^(2B) is absent or a C1-8 alkyl group, a saltthereof, or an N-oxide thereof, or a solvate thereof, or a prodrugthereof;[33] The compound according to the above [31], wherein R¹ is a C4-7monocyclic carbocyclic ring or a C1-8 alkyl group, a salt thereof, or anN-oxide thereof, or a solvate thereof, or a prodrug thereof;[34] The compound according to the above [1], wherein the compoundrepresented by formula (I) is:

-   N′-({1-[(1-cycloheptyl-4-piperidinyl)methyl]-4-piperidinyl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)urea,-   4-[({4-[cycloheptyl(propyl)amino]cyclohexyl}amino)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,-   4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,-   4-{[(1-cycloheptyl-4-piperidinyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,-   1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[8-(2-thienylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzyl)methanamine,-   1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]methanamine,-   4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)-3-methoxybenzamide,-   N′-{trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}-N,N-bis(1H-imidazol-2-ylmethyl)urea,-   4-({[2-(1-cycloheptyl-4-piperidinylidene)ethyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,-   N,N-bis(1H-imidazol-2-ylmethyl)-4-({[trans-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)cyclohexyl]amino}methyl)benzamide,-   N,N-bis(1H-imidazol-2-ylmethyl)-5-{8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}-1-penthanamine,-   N′-[4-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)cyclohexyl]-N,N-bis(1H-imidazol-2-ylmethyl)urea,-   1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzyl)methanamine,-   1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[4.4]non-2-yl}methyl)benzyl]methanamine,-   1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}methanamine,-   2-{[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)amino]methyl}-3-pyridinol,-   1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,-   1-(4-{[8-(2-ethylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,-   N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(1-propylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,-   1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,-   1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]benzyl}methanamine,-   1-{4-[(9-cyclohexyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,-   4-{[9-(2-ethylbutyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,-   1-(1H-imidazol-2-yl)-N-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]benzyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,-   1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-[(1-ethyl-1H-imidazol-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)methanamine,-   1-(4-{[9-(2-ethylbutyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,-   1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isopropyl-1H-imidazol-2-yl)methyl]methanamine,-   1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine,-   1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,-   1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-(2-pyridinylmethyl)methanamine,-   1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(3-methyl-2-pyridinyl)methyl]methanamine,-   N,N-bis(1H-imidazol-2-ylmethyl)-4-({[trans-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)cyclohexyl]amino}methyl)benzenesulfonamide,    or-   1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-2-yl}methyl)benzyl]methanamine,-   a salt thereof, or an N-oxide thereof, or a solvate thereof, or a    prodrug thereof;    [35] The compound according to the above [1], wherein the compound    represented by formula (I) is    trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine    or    trans-4-[(9-cyclohexyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine,    a salt thereof, or an N-oxide thereof, or a solvate thereof, or a    prodrug thereof;    [36] The compound according to the above [1], wherein the compound    represented by formula (I) is:-   1-{1-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]-4-piperidinyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,-   2-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)ethanamine,-   1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,-   1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,-   1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine,-   4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide,-   1-(4-{2-[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-2-oxoethyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,-   4-{[2-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,-   4-{[4-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,    or-   2-(2-{[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)amino]methyl}-1H-imidazol-1-yl)-N,N-dimethylacetamide,-   a salt thereof, or an N-oxide thereof, or a solvate thereof, or a    prodrug thereof;    [37] The compound according to the above [1], wherein the compound    represented by formula (I) is:-   1-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine,-   1-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine,-   1-{3-[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-oxopropanoyl}-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine,-   1-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-N,N-bis(1H-imidazol-2-ylmethyl)-3-pyrrolidinamine,    or-   1-[3-(8-benzyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine,-   a salt thereof, or an N-oxide thereof, or a solvate thereof, or a    prodrug thereof;    [38] A pharmaceutical composition comprising the compound    represented by formula (I) according to the above [1], a salt    thereof, or an N-oxide thereof, or a solvate thereof, or a prodrug    thereof;    [39] The pharmaceutical composition according to the above [38],    which is a CXCR4 antagonist;    [40] The pharmaceutical composition according to the above [39],    which is a preventive and/or therapeutic agent of CXCR4-mediated    diseases, or an agent for regeneration therapy;    [41] The pharmaceutical composition according to the above [40],    wherein the CXCR4-mediated disease is asthma, human immunodeficiency    virus infection, acquired immunodeficiency syndrome, cancer, cancer    metastasis, rheumatoid arthritis, arthritis, retinopathy, macular    degeneration, pulmonary fibrosis, ischemic diseases, systemic    erythematosus or transplanted organ rejection, or the agent for    regeneration therapy is an agent for recruitment of hemopoietic stem    cells to peripheral blood, or an agent for a transplantation medical    treatment;    [42] The pharmaceutical composition according to the above [40],    wherein the CXCR4-mediated diseases is human immunodeficiency virus    infection;    [43] The pharmaceutical composition according to the above [39],    which is a preventive and/or therapeutic agent of cancerous    diseases;    [44] A pharmaceutical composition comprising the compound    represented by formula (I) according to the above [1], a salt    thereof, an N-oxide thereof or a solvate thereof, or a prodrug    thereof, and one or more kinds selected from reverse transcriptase    inhibitor, protease inhibitor, CCR2 antagonist, CCR3 antagonist,    CCR4 antagonist, CCR5 antagonist, CXCR4 antagonist, HIV integrase    inhibitor, fusion inhibitor, CD4 antagonist, antibody against    surface antigen of HIV, Short Interfering RNA targeting a    HIV-related factor, and vaccine of HIV;    [45] A method for antagonizing CXCR4 in a mammal, comprising    administering an effective dosage of the compound represented by    formula (I) according to the above [1], a salt thereof, an N-oxide    thereof or a solvate thereof, or a prodrug thereof to the mammal;    [46] A method of prevention and/or treatment for CXCR4-mediated    diseases in a mammal, comprising administering an effective dosage    of the compound represented by formula (I) according to the above    [1], a salt thereof, an N-oxide thereof or a solvate thereof, or a    prodrug thereof to the mammal;    [47] Use of the compound represented by formula (I) according to the    above [1], a salt thereof, an N-oxide thereof or a solvate thereof    or a prodrug thereof for production of a CXCR4 antagonist;    [48] Use of the compound represented by formula (I) according to the    above [1], a salt thereof, an N-oxide thereof or a solvate thereof    or a prodrug thereof for production of a preventive and/or    therapeutic agent for CXCR4-mediated diseases; and    [49] The method for producing a compound represented by formula (I),    a salt thereof, an N-oxide thereof or a solvate thereof, or a    prodrug thereof.

Effect of the Invention

The compound of the present invention has an antagonistic activityagainst CXCR4 and is therefore useful as a preventive and/or therapeuticagent for diseased mediated by CXCR4, namely, CXCR4-mediated diseases.Furthermore, the compound of the present invention is also useful as apreventive and/or therapeutic agent for cancerous diseases orinfections.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, “bond” means to directly bind withoutmediating the other atom therebetween.

In the present specification, “cyclic group” includes, for example, amonocyclic or condensed cyclic group, a bridged cyclic group, aspiro-bound cyclic group and the like. The “monocyclic or condensedcyclic group” herein includes, for example, a monocyclic or condensedcarbocyclic ring, a monocyclic or condensed heterocyclic ring and thelike. The “monocyclic or condensed carbocyclic ring” includes a C3-15monocyclic or condensed carbocyclic ring. The “C3-15 monocyclic orcondensed carbocyclic ring” includes a C3-15 monocyclic or condensedunsaturated carbocyclic ring, or partially or completely saturated onethereof. Examples of the “C3-15 monocyclic or condensed unsaturatedcarbocyclic ring, or partially or completely saturated one thereof”include, for example, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane,cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene,perhydroindene, indane, naphthalene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, heptalene,perhydroheptalene, biphenylene, as-indacene, s-indacene, acenaphthylene,acenaphthene, fluorene, phenalene, phenanthrene, anthracene, and1,2,3,5,6,7-hexahydro-s-indacene rings. Among these, examples of the“C3-15 monocyclic or condensed aromatic carbocyclic ring” includebenzene, azulene, naphthalene, phenanthrene, anthracene rings and thelike.

The “monocyclic or condensed heterocyclic ring” includes, for example, a3- to 15-membered monocyclic or condensed heterocyclic ring having, as ahetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to2 sulfur atom(s). Examples of the “3- to 15-membered monocyclic orcondensed heterocyclic ring having, as a hetero atom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)” include a3- to 15-membered monocyclic or condensed unsaturated heterocyclic ringhaving, as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s)and/or 1 to 2 sulfur atom(s), or partially or completely saturated onethereof. Examples of the “3- to 15-membered monocyclic or condensedunsaturated heterocyclic ring having, as a hetero atom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s), orpartially or completely saturated one thereof” include, for example,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, β-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine,aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrobenzazepine, tetrahydro benzoazepin, dihydrobenzodiazepine,tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine,tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole,perhydrocarbazole, dihydroacridine, tetrahydroacridine,perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,tetrahydrodibenzofuran, tetrahydrodibenzothiophene,perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane,dithiolane, dithiane, dioxaindane, benzodioxane, chroman,benzodithiolane, benzodithiane, 6,7-dihydro-5H-cyclopenta[b]pyrazine,5H-cyclopenta[b]pyrazine, imidazo[2,1-b][1,3]thiazole,pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine,[1,3]thiazolo[4,5-b]pyrazine, thieno[2,3-b]pyrazine,3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazine,6,7-dihydro-5H-cyclopenta[b]pyrazine, imidazo[1,2-a]pyrazine,6,7-dihydro-5H-cyclopenta[b]pyridine, furo[3,2-b]pyridine,pyrido[2,3-d]pyrimidine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine,5,6,7,8-tetrahydro-1,6-naphthylidine,6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,3,4-dihydro-2H-pyrano[3,2-c]pyridine, 2,3-dihydrofuro[3,2-c]pyridine,hexahydro-1H-pyrrolidine, octahydrocyclopenta[c]pyrrole,octahydrocyclopenta[b]pyrrole, octahydropyrrolo[3,2-b]pyrrole,octahydropyrrolo[3,4-c]pyrrole, hexahydro-2H-furo[3,2-b]pyrrole,hexahydro-2H-thieno[3,2-b]pyrrole, decahydroquinoline,decahydro-2,6-naphthylidine, octahydro-2H-quinolidine,octahydro-1H-pyrido[1,2-c]pyrimidine, octahydro-2H-1,4-benzooxazine,decahydro-1,5-naphthylidine, octahydro-1H-pyrrolo[3,4-b]pyridine,octahydro-1H-pyrrolo[3,4-c]pyridine rings and the like. Among these,examples of the “3- to 15-membered monocyclic or condensed heterocyclicring having, as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygenatom(s) and/or 1 to 2 sulfur atom(s)” include pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, thiadiazole, indole, isoindole, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline,isoquinoline, purine, phthalazine, pteridine, naphthylidine,quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole,benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, carbazole,β-carboline, acridine, phenazine, dibenzofuran, dibenzothiophene,phenanthridine, phenanthroline, perimidine rings and the like.

The “bridged cyclic group” includes a bridged carbocyclic ring and abridged heterocyclic ring. The “bridged carbocyclic ring” includes, forexample, a C4-15 bridged carbocyclic ring. Examples of the “C4-15bridged carbocyclic ring” include bicyclo[2.2.1]heptane,bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hept-2-ene, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane,bicyclo[2.2.2]oct-2-ene, adamantane, noradamantane,bicyclo[2.1.1]hexane, bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane,bicyclo[3.3.2]decane ring and the like.

Examples of the “bridged heterocyclic ring” include, for example, aheterocyclic bridged ring having, as a hetero atom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s). Examples ofthe “heterocyclic bridged ring having, as a hetero atom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)” include,for example, a “4- to 15-membered heterocyclic bridged ring having, as ahetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to2 sulfur atom(s)”. Examples of the “4- to 15-membered heterocyclicbridged ring having, as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2oxygen atom(s) and/or 1 to 2 sulfur atom(s)” includeazabicyclo[2.2.1]heptane, oxabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane,oxabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane,diazabicyclo[2.2.2]octane, 1-azatricyclo[3.3.1.1^(3,7)]decane,3-azabicyclo[3.3.1]nonane, and 3,7-diazabicyclo[3.3.1]nonane rings andthe like.

The “spiro-bound cyclic group” includes a spiro-bound carbocyclic ringand a spiro-bound heterocyclic ring. Examples of the “spiro-boundcarbocyclic ring” include spiro[4.4]nonane, spiro[4.5]decane,spiro[5.5]undecane, spiro[3.4]octane, spiro[3.5]nonane rings and thelike.

The “spiro-bound heterocyclic ring” includes a spiro-bound heterocyclicring having, as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygenatom(s) and/or 1 to 2 sulfur atom(s). The “spiro-bound heterocyclic ringhaving, as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s)and/or 1 to 2 sulfur atom(s)” include a 7- to 15-membered spiro-boundheterocyclic ring having, as a hetero atom, 1 to 4 nitrogen atom(s), 1to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s). Examples of the “7- to15-membered spiro-bound heterocyclic ring having, as a hetero atom, 1 to4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)”herein include azaspiro[4.4]nonane, oxazaspiro[4.4]nonane,dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane,dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazaspiro[4.5]decane,azaspiro[5.5]undecane, oxaspiro[5.5]undecane, dioxaspiro[5.5]undecane,2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane, 2,9-diazaspiro[5.5]undecane,2,8-diazaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane,2,7-diazaspiro[4.4]nonane, 1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 7-azaspiro[4.5]decane, 3-azaspiro[5.5]undecane,2-azaspiro[5.5]undecane, 1-oxa-4,8-diazaspiro[5.5]undecane,1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 2-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 2,3-dihydrospiro[indene-1,4′-piperidine],3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine],3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidine],2-azaspiro[4.5]decane, 2-azaspiro[3.5]nonane,1′,2′-dihydrospiro[cyclohexane-1,3′-indole],2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinoline],1′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-quinoline],1,6-diazaspiro[3.4]octane, 1,5-diazaspiro[3.4]octane,1,7-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.5]nonane,1,5-diazaspiro[3.5]nonane, 1,7-diazaspiro[4.4]nonane,1,6-diazaspiro[4.4]nonane, 1,8-diazaspiro[4.5]decane,1,7-diazaspiro[4.5]decane, 2,6-diazaspiro[3.4]octane,1,6-diazaspiro[4.5]decane, 2,6-diazaspiro[3.5]nonane,1,9-diazaspiro[5.5]undecane, 1,8-diazaspiro[5.5]undecane,6-azaspiro[3.5]nonane, 6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane,1-thia-4,8-diazaspiro[5.5]undecane rings and the like.

In the present specification, “aliphatic hydrocarbon group” includes,for example, “linear or branched aliphatic hydrocarbon group”. Examplesof the “linear or branched aliphatic hydrocarbon group” include“aliphatic hydrocarbon group having 1 to 8 carbon atom(s)”, and examplesof “aliphatic hydrocarbon group having 1 to 8 carbon atom(s)” includeC1-8 alkyl group, C2-8 alkenyl group, and C2-8 alkynyl group.

Examples of the C1-8 alkyl group include methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, and octyl groups, and isomer groups thereof.

Examples of the C2-8 alkenyl group include vinyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl,hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, andoctatrienyl groups, and isomer groups thereof.

Examples of the C2-8 alkynyl group include ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl, butadiynyl, pentadiynyl,hexadiynyl, heptadiynyl, octadiynyl, hexatriynyl, heptatriynyl, andoctatriynyl groups, and isomer groups thereof.

In the present specification, “group having a basic group” representedby A¹ and A² is not specifically limited as long as it has a basicgroup. Examples thereof include (1) basic group, (2) aliphatichydrocarbon group which is substituted with a basic group, and also mayhave a substituent(s), and (3) cyclic group which is substituted with abasic group, and also may have a substituent(s).

The “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon groupwhich is substituted with a basic group, and also may have asubstituent(s)” has the same meaning as in the above aliphatichydrocarbon group.

The “cyclic group” in the “cyclic group which is substituted with abasic group, and also may have a substituent(s)” has the same meaning asin the above cyclic group.

The “substituent” in the “aliphatic hydrocarbon group which issubstituted with a basic group, and also may have a substituent(s)” orthe “cyclic group which is substituted with a basic group, and also mayhave a substituent(s)” is not specifically limited as long as it is asubstituent. Examples thereof include the following substituents definedas T.

Examples of T include:

(1) aliphatic hydrocarbon group,

(2) C1-8 alkylidene group (for example, methylidene, ethylidene,propylidene, butylidene, pentylidene, hexylidene, heptylidene, oroctylidene group, and isomer thereof, etc.),

(3) cyclic group,

(4) aliphatic hydrocarbon group substituted with a cyclic group (forexample, cyclopropylmethyl, cyclopentylmethyl, cyclohexyl methyl,phenylmethyl, naphthylmethyl, pyridinylmethyl, cyclopropylethyl,cyclopentylethyl, cyclohexylethyl, phenylethyl, naphthylethyl,pyridinylethyl, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl,phenylmethyl, phenylpropyl, naphthylpropyl, pyridinylpropyl, etc.),(5) hydroxyl group,(6) —O-aliphatic hydrocarbon group (for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy,heptyloxy, octyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy,propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, etc.),(7) —O-cyclic group (for example, cyclopropyloxy, cyclopentyloxy,cyclohexyloxy, phenoxy, naphthyloxy, pyridinyloxy, etc.),(8) —O-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethoxy, cyclohexylmethoxy, phenylmethoxy, etc.),(9) mercapto group,(10) —S-aliphatic hydrocarbon group (for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio,pentylthio, hexylthio, heptylthio, octylthio, propenylthio, butenylthio,pentenylthio, hexenylthio, propynylthio, butynylthio, pentynylthio,hexynylthio, etc.),(11) —S-cyclic group (for example, cyclopropylthio, cyclopentylthio,cyclohexylthio, phenylthio, naphthylthio, pyridinylthio, etc.),(12) —S-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylthio, cyclohexylmethylthio, phenylmethylthio, etc.),(13) —S(O)-aliphatic hydrocarbon group (for example, methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,isobutylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl,heptylsulfinyl, octylsulfinyl, propenylsulfinyl, butenylsulfinyl,pentenylsulfinyl, hexenylsulfinyl, propynylsulfinyl, butynylsulfinyl,pentynylsulfinyl, hexynylsulfinyl, etc.),(14) —S(O)-cyclic group (for example, cyclopropylsulfinyl,cyclopentylsulfinyl, cyclohexylsulfinyl, phenylsulfinyl,naphthylsulfinyl, pyridinylsulfinyl, etc.),(15) —S(O)-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylsulfinyl, cyclohexylmethylsulfinyl,phenylmethylsulfinyl, etc.),(16) —SO₂-aliphatic hydrocarbon group (for example, methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl,heptylsulfonyl, octylsulfonyl, propenylsulfonyl, butenylsulfonyl,pentenylsulfonyl, hexenylsulfonyl, propynylsulfonyl, butynylsulfonyl,pentynylsulfonyl, hexynylsulfonyl, etc.),(17) —SO₂-cyclic group (for example, cyclopropylsulfonyl,cyclopentylsulfonyl, cyclohexylsulfonyl, phenylsulfonyl,naphthylsulfonyl, pyridinylsulfonyl, etc.),(18) —SO₂-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylsulfonyl, cyclohexylmethylsulfonyl,phenylmethylsulfonyl, etc.),(19) —O—CO-aliphatic hydrocarbon group (for example, methanoyloxy,ethanoyloxy, propanoyloxy, isopropanoyloxy, butanoyloxy, isobutanoyloxy,tert-butanoyloxy, pentenoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy,propenoyloxy, butenoyloxy, pentenoyloxy, hexenoyloxy, propynoyloxy,butynoyloxy, pentynoyloxy, hexynoyloxy, etc.),(20) —O—CO-cyclic group (for example, cyclopropylcarbonyloxy,cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, phenylcarbonyloxy,naphthylcarbonyloxy, pyridinylcarbonyloxy, etc.),(21) —O—CO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethanoyloxy, cyclohexylmethanoyloxy, phenylmethanoyloxy,etc.),(22) —CO-aliphatic hydrocarbon group (for example, methanoyl, ethanoyl,propanoyl, isopropanoyl, butanoyl, isobutanoyl, tert-butanoyl,pentanoyl, hexanoyl, heptanoyl, octanoyl, propenoyl, butenoyl,pentenoyl, hexenoyl, propynoyl, butynoyl, pentynoyl, hexynoyl, etc.),(23) —CO-cyclic group (for example, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, phenylcarbonyl,naphthylcarbonyl, pyridinylcarbonyl, etc.),(24) —CO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethanoyl, cyclohexylmethanoyl, phenylmethanoyl, etc.),(25) oxo group,(26) thioxo group,(27) sulfino group,(28) sulfo group,(29) amino group,(30) mono- or di-substituted amino group (“substituent” in “mono- ordi-substituted amino group” herein includes, for example, (1) aliphatichydrocarbon group, (2) cyclic group, and (3) aliphatic hydrocarbon groupsubstituted with a cyclic group. Examples of “mono- or di-substitutedamino group” include methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino,hexylamino, heptylamino, octylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, dipentylamino, dihexylamino, diheptylamino,dioctylamino, N-methyl-N-ethylamino, cyclopropylamino, cyclopentylamino,cyclohexylamino, phenylamino, diphenylamino, dibenzylamino,N-phenyl-N-methylamino, N-phenyl-N-ethylamino, N-benzyl-N-methylamino,N-benzyl-N-ethylamino, N-cyclohexyl-N-propylamino, etc.),(31) sulfamoyl group,(32) mono- or di-substituted sulfamoyl group (“substituent” in “mono- ordi-substituted sulfamoyl group” include, for example, (1) aliphatichydrocarbon group, (2) cyclic group, and (3) aliphatic hydrocarbon groupsubstituted with a cyclic group. Examples of “mono- or di-substitutedsulfamoyl group” include N-methylsulfamoyl, N-ethylsulfamoyl,N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl,N-isobutylsulfamoyl, N-(tert-butyl)sulfamoyl, N-pentylsulfamoyl,N-hexylsulfamoyl, N-heptylsulfamoyl, N-octylsulfamoyl,N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl,N,N-dibutylsulfamoyl, N,N-dipentylsulfamoyl, N,N-dihexylsulfamoyl,N-methyl-N-ethylsulfamoyl, N-cyclopropylsulfamoyl,N-cyclopentylsulfamoyl, N-cyclohexylsulfamoyl, N-phenylsulfamoyl,N,N-diphenylsulfamoyl, N,N-d ibenzylsulfamoyl,N-phenyl-N-methylsulfamoyl, N-phenyl-N-ethylsulfamoyl,N-benzyl-N-methylsulfamoyl, N-benzyl-N-ethylsulfamoyl,N-cyclohexyl-N-propylsulfamoyl, etc.),(33) carboxyl group,(34) —COO-aliphatic hydrocarbon group (for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl,hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl,propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl,hexenyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl,pentynyloxycarbonyl, hexynyloxycarbonyl, etc.),(35) —COO-cyclic group (for example, cyclopropyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl,naphthyloxycarbonyl, pyridinyloxycarbonyl, etc.),(36) —COO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethoxycarbonyl, cyclohexylmethoxycarbonyl, phenylmethoxycarbonyl, etc.),(37) carbamoyl group,(38) mono- or di-substituted carbamoyl group (“substituent” in “mono- ordi-substituted carbamoyl group” herein includes, for example, (1)aliphatic hydrocarbon group, (2) cyclic group, and (3) aliphatichydrocarbon group substituted with a cyclic group. Examples of “mono- ordi-substituted carbamoyl group” include N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, N-isobutylcarbamoyl, N-(tert-butyl)carbamoyl,N-pentylcarbamoyl, N-hexylcarbamoyl, N-heptylcarbamoyl,N-octylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclopentylcarbamoyl,N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl,N,N-dipentylcarbamoyl, N,N-dihexylcarbamoyl, N-methyl-N-ethylcarbamoyl,N,N-diphenylcarbamoyl, N,N-dibenzylcarbamoyl,N-phenyl-N-methylcarbamoyl, N-phenyl-N-ethylcarbamoyl,N-benzyl-N-methylcarbamoyl, N-benzyl-N-ethylcarbamoyl, etc.),(39) —NH—CO-aliphatic hydrocarbon group (for example, methanoylamino,ethanoylamino, propanoylamino, isopropanoylamino, butanoylamino,isobutanoylamino, tert-butanoylamino, pentanoylamino, hexenoylamino,heptanoylamino, octanoylamino, propenoylamino, butenoylamino,pentenoylamino, hexenoylamino, propynoylamino, butynoylamino,pentynoylamino, hexynoylamino, etc.),(40) —NH—CO-cyclic group (for example, cyclopropylcarbonylamino,cyclopentylcarbonylamino, cyclohexylcarbonylamino, phenylcarbonylamino,naphthylcarbonylamino, pyridinylcarbonylamino, etc.),(41) —NH—CO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethanoylamino, cyclohexylmethanoylamino,phenylmethanoylamino, etc.),(42) —NH—SO₂-aliphatic hydrocarbon group (for example,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino,tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino,heptylsulfonylamino, octylsulfonylamino, propenylsulfonylamino,butenylsulfonylamino, pentenylsulfonylamino, hexenylsulfonylamino,propynylsulfonylamino, butynylsulfonylamino, pentynylsulfonylamino,hexynylsulfonyl, etc.),(43) —NH—SO₂-cyclic group (for example, cyclopropylsulfonylamino,cyclopentylsulfonylamino, cyclohexylsulfonylamino, phenylsulfonylamino,naphthylsulfonylamino, pyridinylsulfonyl, etc.),(44) —NH—SO₂-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylsulfonylamino, cyclohexylmethylsulfonylamino,phenylmethylsulfonyl, etc.),(45) cyano group,(46) hydrazino group,(47) nitro group,(48) nitroso group,(49) imino group,(50) mono-substituted imino group (“substituent” in the mono-substitutedimino group includes, for example, (1) aliphatic hydrocarbon group, (2)cyclic group, (3) aliphatic hydrocarbon group substituted with a cyclicgroup, (4) hydroxyl group, (5) —O-aliphatic hydrocarbon group, (6)—O-cyclic group, and (7) —O-aliphatic hydrocarbon-cyclic group. Examplesof “mono-substituted imino group” include methylimino, ethylimino,propylimino, isopropylimino, butylimino, isobutylimino,(tert-butyl)imino, pentylimino, hexylimino, heptylimino, octylimino,cyclopropylimino, cyclopentylimino, cyclohexylimino, phenylimino,benzylimino, hydroxyimino, ethoxyimino, propoxyimino, isopropoxyimino,butoxyimino, cyclopentoxyimino, cyclohexyloxyimino, phenoxyimino,benzyloxyimino, etc.),(51) halogen atom (for example, fluorine atom, chlorine atom, bromineatom, iodine atom, etc.),(52) methyl group substituted with 1 to 3 halogen atom(s) (for example,fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, etc.),and(53) methoxy group substituted with 1 to 3 halogen atom(s) (for example,fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy,etc.). These optional substituents may be substituted on the optionalsubstitutable position in optional substitutable number. The number ofsubstituents is preferably from 1 to 8, and more preferably from 1 to 5.The “aliphatic hydrocarbon group” and the “cyclic group” in T are asdefined above. Also, “-aliphatic hydrocarbon-” means a divalentaliphatic hydrocarbon group and includes, for example, a divalent groupin which one optional hydrogen atom is further removed from the“aliphatic hydrocarbon group”.

The “basic group” of “(1) basic group”, “(2) aliphatic hydrocarbon groupwhich is substituted with a basic group, and also may have asubstituent(s)”, and “(3) cyclic group which is substituted with a basicgroup, and also may have a substituent(s)” defined as the “group havinga basic group” is not specifically limited as long as it has a basicnitrogen atom. Examples thereof include (a) amino group, (b) amidinogroup, (c) guanidino group, (d) hydrazino group, (e) mono- ordi-substituted amino group, (f) mono-, di- or tri-substituted amidinogroup, (g) mono-, di-, tri- or tetra-substituted guanidino group, (h)mono-, di- or tri-substituted hydrazino group, and (i)nitrogen-containing heterocyclic ring which may have a substituent(s).Examples of the “substituent” in the “mono- or di-substituted aminogroup” herein include (1) aliphatic hydrocarbon group (which is asdefined above), (2) cyclic group (which is as defined above), (3)aliphatic hydrocarbon group substituted with a cyclic group (aliphatichydrocarbon and cyclic group are as defined above), (4) cyclic groupsubstituted with a substituent(s) (substituent has the same meaning asin T, and cyclic group is as defined above), (5) aliphatic hydrocarbongroup substituted with a substituent(s) (substituent has the samemeaning as in T, and aliphatic hydrocarbon is as defined above), (6)aliphatic hydrocarbon group substituted with a cyclic group substitutedwith a substituent(s) (substituent has the same meaning as in T, andaliphatic hydrocarbon and cyclic groups are as defined above), and (7)substituent exemplified as the above T other than the above (1) to (6).These optional substituents may be substituted on the optionalsubstitutable position in optional substitutable number. The number ofsubstituents is preferably from 1 to 8, and more preferably from 1 to 5.Examples thereof include methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino,hexylamino, heptylamino, octylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, dipentylamino, dihexylamino, diheptylamino,dioctylamino, N-methyl-N-ethylamino, cyclopropylamino, cyclopentylamino,cyclohexylamino, phenylamino, diphenylamino, dibenzylamino,N-phenyl-N-methylamino, N-phenyl-N-ethylamino, N-benzyl-N-methylamino,N-benzyl-N-ethylamino, N-benzyl-N-cyclohexylamino,N-cyclohexyl-N-propylamino, N-cyclohexyl-N-(3-hydroxypropyl)amino,N-(4-hydroxycyclohexyl)-N-propylamino,N-(4-hydroxycyclohexyl)-N-(3-hydroxypropyl)amino,N-(4-hydroxycyclohexyl)methyl-N-propylamino, N-cyclohexyl-N-acetylamino,N-(3-methoxypropyl)-N-propylamino, N-(2-carboxyethyl)-N-propylamino,N-(2-ethylpropyl)-N-propylamino, N-cyclohexyl-N-(methylsulfonyl)amino,N-(tetrahydropyran-4-yl)-N-propylamino, andN-(indan-2-yl)-N-propylamino.

Examples of the “substituent” in the “mono-, di- or tri-substitutedamidino group” include (1) aliphatic hydrocarbon group (which is asdefined above), (2) cyclic group (which is as defined above), (3)aliphatic hydrocarbon group substituted with a cyclic group (aliphatichydrocarbon and cyclic groups are as defined above). Examples of the“mono-, di- or tri-substituted amidino group” include methylamidino,ethylamidino, propylamidino, isopropylamidino, butylamidino,isobutylamidino, tert-butylamidino, pentylamidino, hexylamidino,heptylamidino, octylamidino, N,N-dimethylamidino, N,N′-dimethylamidino,N,N,N′-trimethylamidino, N,N-diethylamidino, N,N′-diethylamidino,N,N,N′-triethylamidino, N,N-dipropylamidino, N,N′-dipropylamidino,N,N,N′-tripropylamidino, N,N-dibutylamidino, N,N′-dibutylamidino,N,N,N′-tributylamidino, N,N-dipentylamidino, N,N′-dipentylamidino,N,N,N′-tripentylamidino, N,N-dihexylamidino, N,N′-dihexylamidino,N,N,N′-trihexylamidino, N,N-diheptylamidino, N,N′-diheptylamidino,N,N,N′-triheptylamidino, N,N-dioctylamidino, N,N′-dioctylamidino,N,N,N′-trioctylamidino, N-methyl-N-ethylamidino,N-methyl-N′-ethylamidino, cyclopropylamidino, cyclopentylamidino,cyclohexylamidino, phenylamidino, N,N-diphenylamidino,N,N′-diphenylamidino, N,N,N′-triphenylamidino, N,N-dibenzylamidino,N,N′-dibenzylamidino, N,N,N′-tribenzylamidino,N-phenyl-N′-methylamidino, N-phenyl-N′-ethylamidino,N-benzyl-N-methylamidino, N-benzyl-N-ethylamidino and the like.

Examples of the “substituent” in the “mono-, di-, tri- ortetra-substituted guanidino group” include (1) aliphatic hydrocarbongroup (which is as defined above), (2) cyclic group (which is as definedabove), and (3) aliphatic hydrocarbon group substituted with a cyclicgroup (aliphatic hydrocarbon and cyclic groups are as defined above).Examples of the “mono-, di-, tri- or tetra-substituted guanidino group”include, for example, methylguanidino, ethylguanidino, propylguanidino,isopropylguanidino, butylguanidino, isobutylguanidino,tert-butylguanidino, pentylguanidino, hexylguanidino, heptylguanidino,octylguanidino, N,N-dimethylguanidino, N,N′-dimethylguanidino,N,N,N′-trimethylguanidino, N,N,N′,N″-tetramethylguanidino,N,N-diethylguanidino, N,N′-diethylguanidino, N,N,N′-triethylguanidino,N,N,N′,N″-tetraethylguanidino, N,N-dipropylguanidino,N,N′-dipropylguanidino, N,N,N′-tripropylguanidino,N,N,N′,N″-tetrapropylguanidino, N,N-dibutylguanidino,N,N′-dibutylguanidino, N,N,N′-tributylguanidino,N,N,N′,N″-tetrabutylguanidino, N,N-dipentylguanidino,N,N′-dipentylguanidino, N,N,N′-tripentylguanidino,N,N,N′,N″-tetrapentylguanidino, N,N-dihexylguanidino,N,N′-dihexylguanidino, N,N,N′-trihexylguanidino,N,N,N′,N″-tetrahexylguanidino, N,N-diheptylguanidino,N,N′-diheptylguanidino, N,N,N′-triheptylguanidino,N,N,N′,N″-tetraheptylguanidino, N,N-dioctylguanidino,N,N′-dioctylguanidino, N,N,N′-trioctylguanidino,N,N,N′,N″-tetraoctylguanidino, N-methyl-N-ethylguanidino,N-methyl-N′-ethylguanidino, cyclopropylguanidino, cyclopentylguanidino,cyclohexylguanidino, phenylguanidino, N,N-diphenylguanidino,N,N′-diphenylguanidino, N,N,N′-triphenylguanidino,N,N,N′,N″-tetraphenylguanidino, N,N-dibenzylguanidino,N,N′-dibenzylguanidino, N,N,N′-tribenzylguanidino,N,N,N′,N″-tetrabenzylguanidino, N-phenyl-N′-methylguanidino,N-phenyl-N′-ethylguanidino, N-benzyl-N-methylguanidino,N-benzyl-N-ethylguanidino and the like.

Examples of the “substituent” in the “mono-, di- or tri-substitutedhydrazino group” include (1) aliphatic hydrocarbon group (which is asdefined above), (2) cyclic group (which is as defined above), and (3)aliphatic hydrocarbon group substituted with a cyclic group (aliphatichydrocarbon and cyclic groups are as defined above). Examples of the“mono-, di- or tri-substituted hydrazino group” include, for example,methylhydrazino, ethylhydrazino, propylhydrazino, isopropylhydrazino,butylhydrazino, isobutylhydrazino, tert-butylhydrazino, pentylhydrazino,hexylhydrazino, heptylhydrazino, octylhydrazino, N,N-dimethylhydrazino,N,N′-dimethylhydrazino, N,N,N′-trimethylhydrazino, N,N-diethylhydrazino,N,N′-diethylhydrazino, N,N,N′-triethylhydrazino, N,N-dipropylhydrazino,N,N′-dipropylhydrazino, N,N,N′-tripropylhydrazino, N,N-dibutylhydrazino,N,N′-dibutylhydrazino, N,N,N′-tributylhydrazino, N,N-dipentylhydrazino,N,N′-dipentylhydrazino, N,N,N′-tripentylhydrazino, N,N-dihexylhydrazino,N,N′-dihexylhydrazino, N,N,N′-trihexylhydrazino, N,N-diheptylhydrazino,N,N′-diheptylhydrazino, N,N,N′-triheptylhydrazino, N,N-dioctylhydrazino,N,N′-dioctylhydrazino, N,N,N′-trioctylhydrazino,N-methyl-N-ethylhydrazino, N-methyl-N′-ethylhydrazino,cyclopropylhydrazino, cyclopentylhydrazino, cyclohexylhydrazino,phenylhydrazino, N,N-diphenylhydrazino, N,N′-diphenylhydrazino,N,N,N′-triphenylhydrazino, N,N-dibenzylhydrazino,N,N′-dibenzylhydrazino, N,N,N′-tribenzylhydrazino,N-phenyl-N′-methylhydrazino, N-phenyl-N′-ethylhydrazino,N-benzyl-N-methylhydrazino, N-benzyl-N-ethylhydrazino and the like.

The “nitrogen-containing heterocyclic ring” in the “nitrogen-containingheterocyclic ring which may have a substituent(s)” include, for example,a heterocyclic ring which is a 3- to 11-membered monocyclic or bicyclicheterocyclic ring having, as a hetero atom, at least one nitrogen atom,and also may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s) and has basicity and the like. Example of the “heterocyclic ringwhich is a 3- to 11-membered monocyclic or bicyclic heterocyclic ringhaving, as a hetero atom, at least one nitrogen atom, and also may havean oxygen atom(s) and/or an optionally oxidized sulfur atom(s) and hasbasicity” herein, include pyrrole, imidazole, triazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, oxazole,thiazole, isoxazole, isothiazole, indole, isoindole, quinoline,isoquinoline, benzoxazole, benzothiazole, benzimidazole, aziridine,azetidine, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, perhydroazepine, perhydrodiazepine, indoline,isoindoline, quinazoline, tetrahydroquinoline, perhydroquinoline,tetrahydroisoquinoline, perhydroisoquinoline, tetrahydronaphthyridine,quinoxaline, tetrahydroquinoxaline, dihydrobenzimidazole,perhydrobenzimidazole, carbazole, tetrahydrocarbazole,azabicyclo[3.2.1]octane, quinuclidine, 2,8-diazaspiro[4.5]decane,1,4,9-triazaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane,2,9-diazaspiro[5.5]undecane, 1,6-diazaspiro[3.4]octane,1,5-diazaspiro[3.4]octane, 1,7-diazaspiro[3.5]nonane,1,6-diazaspiro[3.5]nonane, 1,5-diazaspiro[3.5]nonane,1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[4.4]nonane,1,8-diazaspiro[4.5]decane, 1,7-diazaspiro[4.5]decane,2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[4.5]decane,2,6-diazaspiro[3.5]nonane, 1,9-diazaspiro[5.5]undecane,1,8-diazaspiro[5.5]undecane, 6-azaspiro[3.5]nonane,6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane,1-thia-4,8-diazaspiro[5.5]undecane ring and the like.

The “substituent” in the “nitrogen-containing heterocyclic ring whichmay have a substituent(s)” includes, other than those exemplified as forthe above T, (a) aliphatic hydrocarbon group substituted with 1 to 5substituent(s) selected from those exemplified in (5) to (26), (29) to(32) and (37) to (53) of the above T (aliphatic hydrocarbon is asdefined above), (b) cyclic group substituted with 1 to 5 substituent(s)selected from those exemplified in (5) to (26), (29) to (32) and (37) to(53) of the above T (cyclic group is as defined above), (c) aliphatichydrocarbon group substituted with “cyclic group substituted with 1 to 5substituent(s) selected from those exemplified in (5) to (26), (29) to(32) and (37) to (53) of the above T” (aliphatic hydrocarbon is asdefined above). These optional substituents may be substituted on theoptional substitutable position in optional substitutable number. Thenumber of substituents is preferably from 1 to 8, and more preferablyfrom 1 to 5.

In the present specification, the “nitrogen-containing heterocyclic ringwhich may have a substituent(s)” represented by ring A^(1A) and ringA^(2A) has the same meaning as in the “nitrogen-containing heterocyclicring which may have a substituent(s)” defined in the above ring A¹ andring A².

In the present specification, examples of the “substituent” of “animidazole ring which may have a substituent(s), a benzimidazole ringwhich may have a substituent(s), or a pyridine ring which may have asubstituent(s)” represented by ring A^(1B) and ring A^(2B) has the samemeaning as the “substituent” of the “nitrogen-containing heterocyclicring which may have a substituent(s)” defined in the above ring A¹ andring A².

In the present specification, “spacer having a main chain of 1 to 4atom(s)” represented by B¹ and B² mean the space wherein 1 to 4 atom(s)of the main chain are arranged in a line. “Number of atoms of mainchain” is counted so that the number of atoms of the main chain isminimized. For example, it is counted that the number of atoms of1,2-cyclopentylene is 2 and the number of atoms of 1,3-cyclopentylene is3. Examples of the “spacer having a main chain of 1 to 4 atom(s)”include divalent group composed of 1 to 4 group(s) selected optionallyfrom —O—, —S—, —CO—, —SO—, —SO₂—, divalent nitrogen atom which may havea substituent, divalent aliphatic hydrocarbon group having 1 to 4 carbonatom(s) which may have a substituent(s), and divalent 3- to 8-memberedmonocyclic cyclic group which may have a substituent(s), wherein 1 to 4atom(s) of the main chain are arranged in a line.

The “divalent nitrogen atom which may have a substituent” represents, inaddition to —NH—, those wherein hydrogen atom in the “—NH-” group areoptionally substituted with (1) aliphatic hydrocarbon group, (2) cyclicgroup, (3) aliphatic hydrocarbon group substituted with a cyclic group,(4) hydroxyl group, (5) —O-aliphatic hydrocarbon group, (6)-O-cyclicgroup, (7) —O-aliphatic hydrocarbon-cyclic group, (8) —SO₂-aliphatichydrocarbon group, (9) —SO₂-cyclic group, (10) —SO₂-aliphatichydrocarbon-cyclic group, (11) —CO-aliphatic hydrocarbon, (12)—CO-cyclic group, (13) —CO-aliphatic hydrocarbon-cyclic group, (14)carboxyl group, (15) —COO-aliphatic hydrocarbon, (16) —COO-cyclic group,or (17) —COO-aliphatic hydrocarbon-cyclic group, among the substituentsexemplified as for the above-described T.

Furthermore, the “substituent” in the “divalent nitrogen atom which mayhave a substituent” represents those wherein hydrogen atom in the “—NH-”group are optionally substituted with (a) aliphatic hydrocarbon groupsubstituted with 1 to 5 substituent(s) selected from those exemplifiedin (5) to (53) of the above T, (b) cyclic group substituted with 1 to 5substituent(s) selected from those exemplified in (5) to (53) of theabove T, (c) cyclic group substituted with “aliphatic hydrocarbon groupsubstituted with 1 to 5 substituent(s) selected from those exemplifiedin (5) to (53) of the above T”, or (d) aliphatic hydrocarbon groupsubstituted with “a cyclic group substituted with 1 to 5 substituent(s)selected from those exemplified in (5) to (53) of the above T”. The“aliphatic hydrocarbon group”, the “cyclic group” and the “-aliphatichydrocarbon-” are as defined above.

Examples of the “divalent aliphatic hydrocarbon group having 1 to 4carbon atom(s)” in the “divalent aliphatic hydrocarbon group having 1 to4 carbon atom(s) which may have a substituent(s)” include C1-4 alkylenegroup (for example, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, etc.), C2-4alkenylene group (for example, —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—,—(CH₂)₂—CH═CH—, —CH═CH—(CH₂)₂—, —CH₂—CH═CH—CH₂—, etc.), and C2-4alkynylene group (for example, —C═C—, —CH₂—C≡C—, —C≡C—CH₂—,—(CH₂)₂—C≡C—, —C≡C—(CH₂)₂—, —CH₂—C≡C—CH₂—, etc.). Examples of the“substituent” in the “divalent aliphatic hydrocarbon group having 1 to 4carbon atom(s) which may have a substituent(s)” include thoseexemplified as for the above-described T, and these optionalsubstituents may be substituted on the substitutable position and thenumber of substituents is from 1 to 5, and preferably from 1 to 2.

Examples of the “divalent 3- to 8-membered monocyclic cyclic group” inthe “divalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s)” include divalent group which can be obtained byeliminating optional two hydrogen atoms from the “C3-8 monocyclic cyclicgroup”. The two hydrogen atoms may be the ones which bonds the samecarbon atom or which bonds different carbon atoms, the latter ispreferable. Examples of the “C3-8 monocyclic cyclic group” hereininclude “C3-8 monocyclic carbocyclic ring” and “3- to 8-memberedmonocyclic heterocyclic ring”. The “C3-8 monocyclic carbocyclic ring”includes C3-8 monocyclic unsaturated carbocyclic ring, and partially orcompletely saturated one thereof. Examples of the “C3-8 monocyclicunsaturated carbocyclic ring, and partially or completely saturated onethereof” include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene,cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene,cyclooctadiene, and benzene rings. Among these, the “C3-8 monocyclicaromatic carbocyclic ring” includes, for example, benzene ring.

Examples of the “3- to 8-membered monocyclic heterocyclic ring” include“3- to 8-membered monocyclic heterocyclic ring having, as a hetero atom,1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfuratom(s)”. The 3- to 8-membered monocyclic heterocyclic ring having, as ahetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to2 sulfur atom(s)” herein includes 3- to 8-membered monocyclicunsaturated heterocyclic ring having, as a hetero atom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s), andpartially or completely saturated one thereof. Examples of the “3- to8-membered monocyclic unsaturated heterocyclic ring having, as a heteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2sulfur atom(s), and partially or completely saturated one thereof”include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran,oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolysine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithianerings and the like. Among these, examples of the “3- to 8-memberedmonocyclic aromatic heterocyclic ring having, as a hetero atom, 1 to 4nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)”include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, thiadiazole rings and thelike.

Examples of the “3- to 8-membered monocyclic cyclic group” in the“divalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s)” include, for example, cyclohexylene, phenylene,pyrrolidine-diyl, piperidine-diyl. Examples of the “substituent” in the“divalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s)” include, for example, those exemplified as the above T.These optional substituents may be substituted on the optionalsubstitutable position in optional substitutable number. The number ofsubstituents is preferably from 1 to 8, and more preferably from 1 to 5.

In the present specification, “spacer having a main chain of 1 to 10atom(s)” represented by E means the space wherein 1 to 10 atom(s) of themain chain are arranged in a line. “Number of atoms of main chain” iscounted so that the number of atoms of the main chain is minimized. Forexample, it is counted that the number of atoms of

is 4, the number of atoms of

is 6 and the number of atoms of

is 6.

Examples of the “spacer having a main chain of 1 to 10 atom(s)” includedivalent group composed of 1 to 10 group(s) selected optionally from—O—, —S—, —CO—, —SO—, —SO₂—, divalent nitrogen atom which may have asubstituent, divalent aliphatic hydrocarbon group having 1 to 10 carbonatom(s) which may have a substituent(s), and divalent 3- to 15-memberedmonocyclic cyclic group which may have a substituent(s), wherein 1 to 10atom(s) of the main chain are arranged in a line. The “divalent nitrogenatom which may have a substituent” is as defined above. Examples of the“divalent aliphatic hydrocarbon group having 1 to 10 carbon atom(s)” inthe “divalent aliphatic hydrocarbon group having 1 to 10 carbon atom(s)which may have a substituent(s)” include C1-10 alkylene group(methylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, nonamethylene,decamethylene group, and isomers thereof), C2-10 alkenylene group(ethenylene, propenylene, butenylene, pentenylene, hexenylene,heptenylene, octenylene, nonenylene, decenylene group, and isomersthereof), and C2-10 alkynylene group (ethynylene, propynylene,butynylene, pentynylene, hexynylene, heptynylene, octynylene,nonynylene, decynylene group, and isomers thereof). Examples of the“substituent” in the “divalent aliphatic hydrocarbon group having 1 to10 carbon atom(s) which may have a substituent(s)” include thoseexemplified as for T, and these optional substituents may be substitutedon the substitutable position and the number of substituents is from 1to 5, and preferably from 1 to 2.

The “divalent 3- to 15-membered cyclic group” in the “divalent 3- to15-membered cyclic group which may have a substituent(s)” includes, forexample, a divalent group which can be obtained by eliminating optionaltwo hydrogen atoms from the “divalent 3- to 15-membered cyclic group”.The “divalent 3- to 15-membered cyclic group” herein includes, forexample, a C3-15 monocyclic or condensed carbocyclic ring defined above,a C4-15 bridged ring, or a C7-15 spiro-bound carbocyclic ring, a 3- to15-membered monocyclic or condensed heterocyclic ring having, as ahetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to2 sulfur atom(s), a 4- to 15-membered bridged heterocyclic ring having,as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or1 to 2 sulfur atom(s), and a 7- to 15-membered spiro-bound heterocyclicring having, as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygenatom(s) and/or 1 to 2 sulfur atom(s). Examples of the “substituent” inthe “divalent 3- to 15-membered cyclic group which may have asubstituent(s)” include those exemplified as for T, and these optionalsubstituents may be substituted on the substitutable position and thenumber of substituents may be from 1 to 5, and preferably from 1 to 2.

In the present specification, the “divalent 3- to 8-membered monocyclicgroup which may have a substituent(s)” represented by E has the samemeaning as the “divalent 3- to 8-membered monocyclic group which mayhave a substituent(s)” defined in B¹ and B².

In the present specification, the “divalent 9- to 10-membered condensedcyclic ring which may have a substituent(s)” in the “divalent 9- to10-membered condensed cyclic group” represented by E includes, forexample, the divalent group which can be obtained by eliminatingoptional two hydrogen atoms from the “9- to 10-membered condensed cyclicring”. The “9- to 10-membered condensed cyclic group” herein includes a“9- to 10-membered condensed carbocyclic ring” and a “9- to 10-memberedcondensed heterocyclic ring”. The “9- to 10-membered condensedcarbocyclic ring” includes a 9- to 10-membered condensed unsaturatedcarbocyclic ring, and partially or completely saturated one thereof.Examples of the “9- to 10-membered condensed unsaturated carbocyclicring, and partially or completely saturated one thereof” include, forexample, azulene, naphthalene, perhydroazulene, indene, perhydroindene,indan, dihydronaphthalene, teterahydronaphthalene, andperhydronaphthalene ring. The “9- to 10-membered condensed heterocyclicring” includes a 9- to 10-membered condensed unsaturated heterocyclicring having, as a hetero atom, 1 to 4 nitrogen atom(s), 1 to 2 oxygenatom(s) and/or 1 to 2 sulfur atom(s), and partially or completelysaturated one thereof. Examples of the “9- to 10-membered condensedunsaturated heterocyclic ring having, as a hetero atom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s), andpartially or completely saturated one thereof” include, for example,indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole,benzotriazole, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, and perhydrobenzimidazolering.

Examples of the “substituent” in the “divalent 9- to 10-memberedcondensed heterocyclic ring which may have a substituent(s)” representedby E include those exemplified as for T, and these optional substituentsmay be substituted on the substitutable position and the number ofsubstituents may be from 1 to 5, and preferably from 1 to 2.

In the present specification, the “divalent 3- to 8-membered condensedcyclic group which may have a substituent(s)” represented by ring E¹ hasthe same meaning as the “divalent 3- to 8-membered monocyclic cyclicgroup which may have a substituent(s)” in B¹ and B². The “divalent 9- to10-membered condensed cyclic group which may have a substituent(s)”represented by ring E¹ has the same meaning as the “divalent 9- to10-membered condensed cyclic group which may have a substituent(s)” inE.

In the present specification, the “aliphatic hydrocarbon group” in the“pyrrolidine ring which may be substituted by an aliphatic hydrocarbongroup or a piperidine ring which may be substituted by an aliphatichydrocarbon group” represented by ring E⁴ has the same meaning as theabove “aliphatic hydrocarbon group”.

In the present specification, the “spacer having a main chain of 1 to 4atom(s)” represented by L has the same meaning as the “spacer having amain chain of 1 to 4 atom(s)” defined in B¹ and B².

In the present specification, the “group having a basic group” in the“aliphatic hydrocarbon group which is substituted with a group having abasic group, and also may have a substituent(s)”, the “monocyclic orcondensed cyclic group which is substituted with a group having a basicgroup, and also may have a substituent(s)”, the “spiro-bound cyclicgroup which may be substituted with a group having a basic group, andalso may have a substituent(s)”, and the “bridged cyclic group which maybe substituted with a group having a basic group, and also may have asubstituent(s)” represented by J has the same meaning as the above“group having a basic group” defined in A¹ and A². The “aliphatichydrocarbon group” in the “aliphatic hydrocarbon group which issubstituted with a group having a basic group, and also may have asubstituent(s)” herein has the same meaning as the “aliphatichydrocarbon group”. The “monocyclic or condensed cyclic group” in the“monocyclic or condensed cyclic group which is substituted with a grouphaving a basic group, and also may have a substituent(s)” has the samemeaning as the “monocyclic or condensed cyclic group” in the above“cyclic group”. The “spiro-bound cyclic group” in the “spiro-boundcyclic group which may be substituted with a group having a basic group,and also may have a substituent(s)” has the same meaning as the“spiro-bound cyclic group” in the above “cyclic group”. The “bridgedcyclic group” of the “bridged cyclic group which may be substituted witha group having a basic group, and also may have a substituent(s)” hasthe same meaning as the “bridged cyclic group” in the “cyclic group”.The “substituent” herein is not specifically limited. Examples thereofinclude (1) an aliphatic hydrocarbon group which may have asubstituent(s), (2) a cyclic group which may have a substituent(s), (3)an aliphatic hydrocarbon group substituted by a cyclic group which mayhave a substituent(s) and (4) substituent exemplified as the above Tother than the above. The “aliphatic hydrocarbon group” and the “cyclicgroup” herein the “aliphatic hydrocarbon group which may have asubstituent(s)”, the “cyclic group which may have a substituent(s)” andthe “aliphatic hydrocarbon group substituted by a cyclic group which mayhave a substituent(s)” have the same meaning as described above. The“substituent” in the above (1) to (3) includes those exemplified as forT, and these optional substituents may be substituted on thesubstitutable position and the number of substituents may be from 1 to5.

In the present specification, ring J¹ and ring J² represent a ring whichforms a spiro-bound cyclic group.

In the present specification, the “C3-10 monocyclic or bicycliccarbocyclic ring” represented by ring J¹ includes a C3-10 monocyclic orbicyclic unsaturated carbocyclic ring, and partially or completelysaturated one thereof. Examples thereof include, for example, benzene,azulene, naphthalene, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, pentalene, perhydropentalene,perhydroazulene, indene, perhydroindene, indane, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, heptalene, perhydroheptaleneand the like.

In the present specification, the “3- to 10-membered monocyclic orbicyclic heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s)” represented byring J¹ includes a 3- to 10-membered monocyclic or bicyclic unsaturatedheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), and partially or completelysaturated one thereof. Examples thereof include, for example, furan,pyran, oxepine, thiophene, thiopyran, thiepine, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene,chromene, benzoxepine, benzothiepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, oxathiane, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, benzoxathiane, benzodioxepane, dioxolane,dioxane, dithiolane, dithiane, dioxaindane, benzodioxane, chroman,benzodithiolane, benzodithiane and the like.

In the present specification, the “3- to 10-membered monocyclic orbicyclic heterocyclic ring which has at least one nitrogen atom and alsomay have an oxygen atom(s) or an optionally oxidized sulfur atom(s)”represented by ring J¹ includes a 3- to 10-membered monocyclic orbicyclic unsaturated heterocyclic ring which has at least one nitrogenatom and also may have an oxygen atom(s) or an optionally oxidizedsulfur atom(s), and partially or completely saturated one thereof.Examples thereof include, for example, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, indazole, quinoline,isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzoxazepine, benzoxadiazepine,benzothiepine, benzothiazepine, benzothiadiazepine, benzoazepine,benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole and thelike.

The “C3-10 monocyclic or bicyclic carbocyclic ring”, “3- to 10-memberedmonocyclic or bicyclic heterocyclic ring composed of a carbon atom(s),an oxygen atom(s) and/or an optionally oxidized sulfur atom(s)”, or “3-to 10-membered monocyclic or bicyclic heterocyclic ring which has atleast one nitrogen atom and also may have an oxygen atom(s) or anoptionally oxidized sulfur atom(s)” in the “C3-10 monocyclic or bicycliccarbocyclic ring, which is substituted with a group having a basicgroup”, “3- to 10-membered monocyclic or bicyclic heterocyclic ringcomposed of a carbon atom(s), an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s), which is substituted with a group having abasic group”, or “3- to 10-membered monocyclic or bicyclic heterocyclicring which has at least one nitrogen atom and also may have an oxygenatom(s) or an optionally oxidized sulfur atom(s), and also which may besubstituted with a group having a basic group” represented by ring J² isas defined above. The “group having a basic group” here has the samemeaning as the “group having a basic group” defined in A¹ and A².

In the present specification, the “bridged carbocyclic ring” in the“bridged carbocyclic ring substituted with a group having a basic group”represented by ring J³ has the same meaning as in the above-described“bridged carbocyclic ring” in the “cyclic group”.

In the present specification, examples of the “bridged heterocyclic ringcomposed of a carbon atom(s), an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s)” of the “bridged heterocyclic ring composed of acarbon atom(s), an oxygen atom(s) and/or an optionally oxidized sulfuratom(s), which is substituted with a group having a basic group”represented by ring J³ include, for example, oxabicyclo[2.2.1]heptaneoxabicyclo[3.2.1]octane and the like.

In the present specification, examples of the “bridged heterocyclic ringwhich has at least one nitrogen atom and also may have an oxygen atom(s)and/or an optionally oxidized sulfur atom(s)” of the “bridgedheterocyclic ring which has at least one nitrogen atom and also may havean oxygen atom(s) and/or an optionally oxidized, which may besubstituted with a group having a basic group” represented by ring J³include, for example, azabicyclo[2.2.1]heptane,oxabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane,azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane,azabicyclo[2.2.2]octane, diazabicyclo[2.2.2]octane,1-azatricyclo[3.3.1.1^(3,7)]decane, 3-azabicyclo[3.3.1]nonane,3,7-diazabicyclo[3.3.1]nonane and the like.

The “group having a basic group” in ring J³ has the same meaning as inthe “group having a basic group” in the above-described A¹ and A².

In the present specification, the “C3-15 monocyclic or condensedcarbocyclic ring” in the “C3-15 monocyclic or condensed carbocyclic ringsubstituted with a group having a basic group” represented by ring J⁴has the same meaning as in the “C3-15 monocyclic or condensedunsaturated carbocyclic ring, and partially or completely saturated onethereof” in the “cyclic group”.

In the present specification, the “3- to 15-membered monocyclic orcondensed heterocyclic ring” of the “3- to 15-membered monocyclic orcondensed heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s), which issubstituted with a group having a basic group” represented by ring J⁴includes a 3- to 15-membered monocyclic or condensed unsaturatedheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), and partially or completelysaturated one thereof. Examples thereof include, for example, furan,pyran, oxepine, thiophene, thiopyran, thiepine, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene,chromene, benzoxepine, benzothiepine, dibenzofuran, xanthene,dibenzothiophene, phenoxathiin, thianthrene, oxirane, oxetane,dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, oxathiane, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, benzoxathiane, benzodioxepane,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,dioxaindane, benzodioxane, chroman, benzodithiolane, benzodithiane andthe like.

In the present specification, the “3- to 15-membered monocyclic orcondensed heterocyclic ring which has at least one nitrogen atom andalso may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s)” of the “3- to 15-membered monocyclic or condensed heterocyclicring which has at least one nitrogen atom and also may have an oxygenatom(s) and/or an optionally oxidized sulfur atom(s), which may besubstituted with a group having a basic group” represented by ring J⁴includes a monocyclic or condensed 3- to 15-membered unsaturatedheterocyclic ring which has at least one nitrogen atom and also may havean oxygen atom(s) and/or an optionally oxidized sulfur atom(s), andpartially or completely saturated one thereof. Examples thereof include,for example, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, azepin, diazepin, oxazole,isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine,oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine,thiazepine, thiadiazepin, indole, isoindole, indolizine, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzoxazepine, benzoxadiazepine,benzothiazepin, benzothiadiazepine, benzoxazepine, benzodiazepine,benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline,acridine, phenazine, phenothiazine, phenoxazine, phenanthridine,phenanthroline, perimidine, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole,tetrahydrocarbazole, perhydrocarbazole, dihydroacridine,tetrahydroacridine, perhydroacridine, hexahydro-1H-pyrrolidine,octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole,octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole,hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-thieno[3,2-b]pyrrole,decahydroquinoline, decahydro-2,6-naphthylidine,octahydro-2H-quinolidine, octahydro-1H-pyrido[1,2-c]pyrimidine,octahydro-2H-1,4-benzooxazine, decahydro-1,5-naphthylidine,octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-1H-pyrrolo[3,4-c]pyridineand the like.

The “group having a basic group” in ring J⁴ has the same meaning as inthe “group having a basic group” in the above-described A¹ and A².

In the present specification,

represents

(in the group, L^(A1) represents -(an aliphatic hydrocarbon group having1 to 3 carbon atom(s) which may have a substituent(s))-(a nitrogen atomwhich may have a substituent(s))-, ring J^(1a) and ring J^(2a) eachindependently represents (i) a C3-10 monocyclic or bicyclic carbocyclicring, or (ii) a 3- to 10-membered monocyclic or bicyclic heterocyclicring composed of a carbon atom(s), an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s), R^(A) represents a group having abasic group, ring J^(1a) and ring J^(2a) may have, in addition to R^(A),1 to 8 substituent(s) on the substitutable position, and when two ormore substituents are present, plural substituents may be the same ordifferent, wherein a nitrogen atom which may have a substituent(s)) inL^(A1) is bonded to ring J^(1a),

(in the group, L^(A2) is as define above, ring J^(1b) represents a 3- to10-membered monocyclic or bicyclic heterocyclic ring which has at leastone nitrogen atom and also may have an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s), ring J^(1b) may have 1 to 8substituent(s) on the substitutable position, and when two or moresubstituents are present, plural substituents may be the same ordifferent, and other symbols are as defined above),

(in the group, ring J^(2b) represents a 3- to 10-membered monocyclic orbicyclic heterocyclic ring which has at least one nitrogen atom and alsomay have an oxygen atom(s) or an optionally oxidized sulfur atom(s), andwhich may be substituted with a group having a basic group, ring J^(2b)may have 1 to 8 substituent(s) on the substitutable position, and whentwo or more substituents are present, plural substituents may be thesame or different, and other symbols are as defined above), or

(in the group, all symbols are as defined above).

includes, for example,

(in the group, all symbols are as defined above).

Includes, for example,

(in the group, all symbols are as defined above, provided that L^(A2)may be a substituent of a nitrogen atom of —NH—),

Includes, for example,

(in the group, all symbols are as defined above, provided that anitrogen atom of —NH— may have a substituent), and

Includes, for example,

(in the group, all symbols are as defined above, provided that L^(A2)may be a substituent of a nitrogen atom of —NH—, and a nitrogen atom of—NH— may have a substituent).

In the present specification, “-(nitrogen atom which may have asubstituent)-” in “-(aliphatic hydrocarbon group having 1 to 3 carbonatom(s) which may have a substituent(s))-(nitrogen atom which may have asubstituent)-” represented by L^(A) and L^(A1) has the same meaning asin the “divalent nitrogen atom which may have a substituent”. Examplesof the “aliphatic hydrocarbon group having 1 to 3 carbon atom(s)” in the“aliphatic hydrocarbon group having 1 to 3 carbon atom(s) which may havea substituent(s)” include C1 to 3 alkylene group (for example,methylene, ethylene, trimethylene, etc.), C2-3 alkenylene group (forexample, ethenylene, propenylene, etc.), and C2-3 alkynylene group (forexample, ethynylene, propynylene, etc.). Examples of the “substituent”in the “aliphatic hydrocarbon group having 1 to 3 carbon atom(s) whichmay have a substituent(s)” include those exemplified as for T, and theseoptional substituents may be substituted on the substitutable positionand the number of substituents is from 1 to 3.

In the present specification, the “divalent aliphatic hydrocarbon grouphaving 1 to 4 carbon atom(s) which may have a substituent(s)”represented by L^(A) and L^(A2) is as defined above.

In the present specification, the “(i) C3-10 monocyclic or bicycliccarbocyclic ring or (ii) 3- to 10-membered monocyclic or bicyclicheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s)” represented by ring J^(1a) andring J^(2a) has the same meaning as in the “(i) C3-10 monocyclic orbicyclic carbocyclic ring or (ii) 3- to 10-membered monocyclic orbicyclic heterocyclic ring composed of a carbon atom(s), a oxygenatom(s) and/or an optionally oxidized sulfur atom(s)” in ring J¹.

In the present specification, the “3- to 10-membered monocyclic orbicyclic heterocyclic ring which has at least one nitrogen atom, andalso may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s)” represented by ring J^(1b) has the same meaning as in the “3-to 10-membered monocyclic or bicyclic heterocyclic ring which has atleast one nitrogen atom and also may have an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s)” in ring J¹.

In the present specification, “3- to 10-membered monocyclic or bicyclicheterocyclic ring which has at least one nitrogen atom and also may havean oxygen atom(s) or an optionally oxidized sulfur atom(s)” representedby ring J^(2b) has the same meaning as in the “3- to 10-memberedmonocyclic or bicyclic heterocyclic ring which has at least one nitrogenatom and also may have an oxygen atom(s) or an optionally oxidizedsulfur atom(s), and which may be substituted with a group having a basicgroup” in ring J².

In the present specification, the “group having a basic group” of R^(A)has the same meaning as in the “group having a basic group” in A¹ andA².

In the present specification, the “spiro-bound cyclic group which may besubstituted with a group having a basic group, and also may have asubstituent(s)” and the “bridged cyclic group which may be substitutedwith a group having a basic group, and also may have a substituent(s)”of J⁵ have the same meaning as the “spirocyclic group which may besubstituted with a group having a basic group, and also may have asubstituent(s)” and the “bridged cyclic group which may be substitutedwith a group having a basic group, and also may have a substituent(s)”in the above-described J.

In the present specification, the “substituent” of the “may have 1 to 8substituent(s) on the substitutable position” of ring J¹, ring J², ringJ³, ring J⁴, ring J^(1a), ring J^(1b), ring J^(2a) and ring J^(2b) isnot specifically limited. Examples thereof include those exemplified asfor T, and these optional substituents may be substituted on thesubstitutable position and the number of substituents is preferably from1 to 8, and more preferably from 1 to 5. When ring J², ring J³, ring J⁴and ring J^(2b) are substituted with a group having a basic group, theseoptional substituents may be substituted on the substitutable positionand the number of substituents is, in addition to a group having a basicgroup, preferably from 1 to 8, and more preferably from 1 to 4.

In the present specification, the “carbon atom which may have asubstituent(s)” represented by G represents, in addition to —CH₂—, thosewherein two hydrogen atoms in the “—CH₂—” group are, each independently,optionally substituted with an aliphatic hydrocarbon group, an aliphatichydrocarbon group substituted with a cyclic group, a hydroxyl group, an—O-aliphatic hydrocarbon group, a mercapto group, a —S-aliphatichydrocarbon group, a —S(O)-aliphatic hydrocarbon-cyclic group, a—SO₂-aliphatic hydrocarbon group, a —CO-aliphatic hydrocarbon group, acarboxyl group, a —COO-aliphatic hydrocarbon group, a cyano group, anitro group, a halogen atom, a methyl group which is substituted with 1to 3 halogen atom(s), or a methoxy group which is substituted with 1 to3 halogen atom(s). These substituents exemplified herein are the samemeaning as the substituents exemplified in the above described T.

In the present specification, the “nitrogen atom which may have asubstituent(s)” represented by G represents, in addition to —NH—, thosewherein a hydrogen atom in the “—NH-” group are optionally substitutedwith an aliphatic hydrocarbon group, an aliphatic hydrocarbon groupsubstituted with a cyclic group, an —O-aliphatic hydrocarbon group, a—SO₂-aliphatic hydrocarbon group, a —CO-aliphatic hydrocarbon group, a—COO-aliphatic hydrocarbon group, a nitro group, or a methyl group whichis substituted with 1 to 3 halogen atom(s). These substituentsexemplified herein are the same meaning as the substituents exemplifiedin the above described T.

In the present specification, “(carbon atom which may have asubstituent(s))” of “-(carbon atom which may have asubstituent(s))-(nitrogen atom which may have a substituent(s))-”represented by G has the same meaning as the “carbon atom which may havea substituent(s)”. The “(nitrogen atom which may have a substituent(s))”of “-(carbon atom which may have a substituent(s))-(nitrogen atom whichmay have a substituent(s))-” has the same meaning as the “nitrogen atomwhich may have a substituent(s)”.

In the present specification, the “optionally oxidized sulfur atom”means —S—, —SO— and —SO₂—.

In the present specification, “substituent” represented by R¹ is notspecifically limited. Examples thereof include (1) an aliphatichydrocarbon group which may have a substituent(s), (2) a cyclic groupwhich may have a substituent(s), (3) an aliphatic hydrocarbon groupsubstituted by a cyclic group which may have a substituent(s), and (4)substituent exemplified as the above T other than the above (1) to (3).The “aliphatic hydrocarbon group” and the “cyclic group” herein the“aliphatic hydrocarbon group which may have a substituent(s)”, the“cyclic group which may have a substituent(s)” and the “aliphatichydrocarbon group substituted by a cyclic group which may have asubstituent(s)” have the same meaning as described above. The“substituent” in (1) to (3) includes those exemplified as for T, andthese optional substituents may be substituted on the substitutableposition and the number of substituents may be from 1 to 5.

In the present specification, the “C4-7 monocyclic carbocyclic ring”represented by R¹ include cyclobutane, cyclopentane, cyclohexane,cycloheptane, benzene ring and the like.

In the present specification, the “C1-8 alkyl group” represented by R¹is as defined above.

In the present specification, the “halogen atom” and the aliphatichydrocarbon group” represented by R^(E) are as defined above.

The present invention further relates to:

[50] the compound according to the above-described [1], wherein J is aspiro-bound cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s), or a bridged cyclicgroup which may be substituted with a group having a basic group, andalso may have a substituent(s);[51] the compound according to the above-described [50], wherein J is aspiro-bound heterocyclic ring or a bridged heterocyclic ring which hasat least one nitrogen atom, and also may have an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), which may be substituted with agroup having a basic group;[52] the compound according to the above-described [50], wherein J is aspiro-bound carbocyclic ring or bridged carbocyclic ring which issubstituted with a group having a basic group, and also may have asubstituent(s);[53] the compound according to the above-described [51], wherein thespiro-bound heterocyclic ring or bridged heterocyclic ring which have atleast one nitrogen atom, and also may have an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s) is:

[54] the compound according to the above-described [51], wherein thespiro-bound heterocyclic ring is (i) a monocyclic cyclic ring composedof at least one nitrogen atom and carbon atom and/or (ii) a 7- to15-membered spiro-bound bicyclic heterocyclic ring which consists of amonocyclic cyclic ring composed of at least one nitrogen atom, oneoxygen atom and carbon atoms;[55] The compound according to the above-described [54], wherein the 7-to 15-membered spiro-bound bicyclic heterocyclic ring is:

and[56] the compound according to the above-described [52], wherein thespiro-bound carbocyclic ring or bridged carbocyclic ring is:

In the present specification, the “spiro-bound heterocyclic ring orbridged heterocyclic ring which has at least one nitrogen atom, and alsomay have an oxygen atom(s) and/or an optionally oxidized sulfur atom(s)”in the “spiro-bound heterocyclic ring or bridged heterocyclic ring whichhas at least one nitrogen atom and also may have an oxygen atom(s)and/or an optionally oxidized sulfur atom(s), which may be substitutedwith a group having a basic group and also may have a substituent(s)”represented by J includes spiro-bound heterocyclic ring which has atleast one nitrogen atom and may also have an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s), and bridged heterocyclic ring whichhas at least one nitrogen atom, and also may have an oxygen atom(s)and/or an optionally oxidized sulfur atom(s). Examples of the“spiro-bound heterocyclic ring which has at least one nitrogen atom andalso may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s)” include, for example, azaspiro[4.4]nonane,oxazaspiro[4.4]nonane, azaspiro[4.5]decane, oxazaspiro[4.5]decane,azaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane,2,8-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane-2,9-diazaspiro[5.5]undecane,2,8-diazaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane,2,7-diazaspiro[4.4]nonane, 1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 8-azaspiro[4.5]decane, 7-azaspiro[4.5]decane,3-azaspiro[5.5]undecane, 2-azaspiro[5.5]undecane,1-oxa-4,8-diazaspiro[5.5]undecane, 1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 2-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 2,3-dihydrospiro[indene-1,4′-piperidine],3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine],3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidine],2-azaspiro[4.5]decane, 2-azaspiro[3.5]nonane,1′,2′-dihydrospiro[cyclohexane-1,3′-indole],2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinoline],1′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-quinoline],1,6-diazaspiro[3.4]octane, 1,5-diazaspiro[3.4]octane,1,7-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.5]nonane,1,5-diazaspiro[3.5]nonane, 1,7-diazaspiro[4.4]nonane,1,6-diazaspiro[4.4]nonane, 1,8-diazaspiro[4.5]decane,1,7-diazaspiro[4.5]decane, 2,6-diazaspiro[3.4]octane,1,6-diazaspiro[4.5]decane, 2,6-diazaspiro[3.5]nonane,1,9-diazaspiro[5.5]undecane, 1,8-diazaspiro[5.5]undecane,6-azaspiro[3.5]nonane, 6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane,1-thia-4,8-diazaspiro[5.5]undecane and the like. Examples of the“bridged heterocyclic ring which has at least one nitrogen atom, andalso may have an oxygen atom and/or a sulfur atom include, for example,azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane,azabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane,diazabicyclo[2.2.2]octane, 1-azatricyclo[3.3.1.1^(3,7)]decane,3-azabicyclo[3.3.1]nonane, 3,7-diazabicyclo[3.3.1]nonane and the like.

In the present specification, the “7- to 15-membered bicyclicspiro-bound heterocyclic ring wherein a ring comprising the spiro-boundheterocyclic ring is (i) a monocyclic cyclic ring composed of at leastone nitrogen atom and carbon atoms, and/or (ii) a monocyclic cyclic ringcomposed of at least one nitrogen atom, one oxygen atom and carbonatoms” represented by J includes (1) 7- to 15-membered bicyclicspiro-bound heterocyclic ring which consists of two spiro-bound (a) 4-to 8-membered monocyclic cyclic rings composed of at least one nitrogenatom and carbon atoms, (2) 7- to 15-membered bicyclic spiro-boundheterocyclic ring which consists of spiro-bound (a) 4- to 8-memberedmonocyclic cyclic ring composed of at least one nitrogen atom and carbonatoms, and (b) 4- to 8-membered monocyclic cyclic ring composed of atleast one nitrogen atom, one oxygen atom and carbon atoms, and (3) 7- to15-membered bicyclic spiro-bound heterocyclic ring which consists of twospiro-bound (b) monocyclic cyclic rings composed of at least onenitrogen atom, one oxygen atom and carbon atoms

“(1) 7- to 15-membered bicyclic spiro-bound heterocyclic ring wherein aring comprising the spiro-bound heterocyclic ring is two (a) 4- to8-membered monocyclic cyclic rings composed of at least one nitrogenatom and carbon atoms” means that two rings selected optionally from“(a) 4- to 8-membered monocyclic cyclic ring composed of at least onenitrogen atom and carbon atoms” share one carbon atom. The shared carbonatom may be any carbon atom as long as it is a carbon atom constitutingthe monocyclic cyclic ring.

“(2) 7- to 15-membered bicyclic spiro-bound heterocyclic ring whichconsists of spiro-bound (a) 4- to 8-membered monocyclic cyclic ringcomposed of at least one nitrogen atom and carbon atoms, and (b) 4- to8-membered monocyclic cyclic ring composed of at least one nitrogenatom, one oxygen atom and carbon atoms” means that one ring selectedoptionally from “(a) 4- to 8-membered monocyclic cyclic ring composed ofat least one nitrogen atom and carbon atoms” and one ring selectedoptionally from “(b) 4- to 8-membered monocyclic cyclic ring composed ofat least one nitrogen atom, one oxygen atom and carbon atoms” share onecarbon atom. The shared carbon atom may be any carbon atom as long as itis a carbon atom constituting the monocyclic cyclic ring.

“(3) 7- to 15-membered bicyclic spiro-bound heterocyclic ring whichconsists of two spiro-bound (b) monocyclic cyclic rings composed of atleast one nitrogen atom, one oxygen atom and carbon atoms” means thattwo rings selected optionally from “(b) monocyclic cyclic ring composedof at least one nitrogen atom, one oxygen atom and carbon atoms” sharesone carbon atom. The shared carbon atom may be any carbon atom as longas it is a carbon atom constituting the monocyclic cyclic ring.

In addition, examples of the “(a) 4- to 8-membered monocyclic cyclicring composed of at least one nitrogen atom and carbon atoms” include,for example, azetidine, pyrrolidine, piperidine, piperazine, azepane,1,4-diazepane, azocane, 1,4-diazocane, 1,5-diazocane, and the like; andexamples of the “(b) 4- to 8-membered monocyclic cyclic ring composed ofat least one nitrogen atom, one oxygen atom and carbon atoms” include,for example, 1,4-oxazepane, 1,4-oxazocane, 1,5-oxazocane, morpholine andthe like.

Examples of the above described “(1) 7- to 15-membered bicyclicspiro-bound heterocyclic ring which consists of two spiro-bound (a) 4-to 8-membered monocyclic cyclic rings composed of at least one nitrogenatom and carbon atoms” represented by J, include, for example,2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane, 2,9-diazaspiro[5.5]undecane,2,8-diazaspiro[5.5]undecane, 2,6-diazaspiro[3.5]nonane,3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane,1,3,8-triazaspiro[4.5]decane, 1,4,9-triazaspiro[5.5]undecane and thelike.

Examples of the above described “(2) 7- to 15-membered bicyclicspiro-bound heterocyclic ring which consists of spiro-bound (a) 4- to8-membered monocyclic cyclic ring composed of at least one nitrogen atomand carbon atoms, and (b) 4- to 8-membered monocyclic cyclic ringcomposed of at least one nitrogen atom, one oxygen atom and carbonatoms” represented by J, include 1-oxa-4,9-diazaspiro[5.5]undecane,1-oxa-4,8-diazaspiro[5.5]undecane and the like.

Examples of the above described “(3) 7- to 15-membered bicyclicspiro-bound heterocyclic ring which consists of two spiro-bound (b)monocyclic cyclic rings composed of at least one nitrogen atom, oneoxygen atom and carbon atoms” represented by J, include2,9-dioxa-5,12-diazaspiro[6.6]tridecane and the like.

In the present invention, all isomers are included unless otherwisespecified. For example, alkyl group, alkenyl group, alkynyl group,alkylene group, alkenylene group, alkynylene group, alkylidene group andthe like include those which are linear and branched. Furthermore, allof isomers (E-, Z-, cis-, and trans-isomers) on the double bond, ringand condensed ring, isomers (R-isomer, S-isomer, α,β configuration,enantiomer, and diastereomer) due to the presence of asymmetric carbon,optically active substances with optical rotation (D-, L-, d-, andI-compounds), polar compounds (high polar compound and low polarcompound) generated by chromatographic separation, equilibriumcompounds, rotational isomers, mixtures in an optional mixing ratio andracemic mixtures are included in the present invention.

In the present invention, as is apparent to those skilled in the art,the symbol

represents that it is bonded to the other side of the page (namely, αconfiguration), the symbol

represents that it is bonded to this side of the page (namely, βconfiguration), the symbol

represents that it is a mixture of the α configuration and the βconfiguration, and

represents that it is bonded to the other side of the page (namely, αconfiguration) or this side of the page (namely, β configuration) withthe proviso that its absolute configuration is not determined.

[Salts]

Salts of the compound represented by formula (I) include all of nontoxicsalts and pharmaceutically acceptable salts. The pharmaceuticallyacceptable salt is preferably a water soluble salt which shows lesstoxicity. Examples of the suitable salt of the compound represented byformula (I) include salts of alkali metal (potassium, sodium, lithium,etc.), salts of alkali earth metal (calcium, magnesium, etc.), ammoniumsalts (tetramethylammonium salt, tetrabutylammonium salt, etc.), saltsof organic amine (triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine, N-methyl-D-glucamine, etc.), acid addition salts[inorganic acid salts (hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, nitrate, etc.), and organic acid salts (acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucuronate, gluconate, etc.)] and thelike.

Furthermore, salts include quaternary ammonium salts. The quaternaryammonium salt is obtained by quaternizing a nitrogen atom of thecompound represented by formula (I) with a R⁰ group (R⁰ group representsa C1-8 alkyl group, or a C1-8 alkyl group substituted with a phenylgroup).

Also, salts include N-oxide. The compound of the present invention canbe converted into N-oxide by an optional method. N-oxide is obtained byoxidizing a nitrogen atom of the compound represented by formula (I).

Examples of suitable solvate of the compound represented by formula (I)include solvates such as water, alcoholic solvent (for example,methanol, ethanol, etc.) and the like. The solvate is preferablynontoxic and water soluble. The solvate of the compound of the presentinvention also includes solvates of alkali (earth) metal salts, ammoniumsalts, salts of organic amine, and acid addition salts of the compoundof the present invention.

The compound of the present invention can be converted into the abovesalts and solvates by a known method.

[Prodrugs]

A prodrug of the compound represented by formula (I) means a compoundwhich is converted into the compound represented by formula (I) in theliving body by the reaction with an enzyme, gastric acid or the like.Examples of the prodrug of the compound represented by formula (I)include compound wherein an amino group is acylated, alkylated, orphosphorylated (for example, compound wherein an amino group of thecompound represented by formula (I) is eicosanoylated, alanylated,pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, etc.) when the compound representedby formula (I) has an amino group; compound wherein a hydroxyl group isacylated, alkylated, phosphorylated, boricated or the like (for example,compound wherein a hydroxyl group of the compound represented by formula(I) is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated,etc.) when the compound represented by formula (I) has a hydroxyl group;and compound wherein a carboxy group is esterificated, amidated or thelike (for example, compound wherein a carboxy group of the compoundrepresented by formula (I) is ethylesterificated, phenylesterificated,carboxymethylesterificated, dimethylaminomethylesterificated,pivaloylcoymethylesterificated, ethoxycarbonyloxyethylesterificated,phthalidylesterificated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterificated,cyclohexyloxycarbonylethylesterificated, methylamidated, etc.) when thecompound represented by formula (I) has a carboxy group. These compoundscan be prepared by a per se known method. The prodrug of the compoundrepresented by formula (I) may be either of a hydrate and a non-hydrate.Also, the prodrug of the compound represented by formula (I) may beconverted into the compound represented by formula (I) underphysiological conditions described in “Development of Drug” published in1990 by Hirokawa Shoten, Vol. 7, “Molecular Design”, pp. 163-198.Furthermore, the compound represented by formula (I) may be labelledwith isotope (for example, ³H, ¹⁴C, ³⁵S, ¹²⁵I, etc.) and the like.

The compound represented by formula (I) of the present invention, a saltthereof, a solvate thereof, or a prodrug thereof (hereinafterabbreviated to a compound of the present invention, sometimes) is acompound which is excellent in solubility and oral absorption andmaintain its pharmacological activity for a long period of time, and isalso less likely to be inhibited by a drug metabolizing enzyme and haslow toxicity. These properties are most important physical, chemical andpharmacological properties required when preparations are developed, andthe inventive compound satisfies these conditions and is expected to beuseful for developing extremely excellent (see The Merck Manual ofDiagnosis and Therapy (17th Ed.), Merck & Co.).

The fact that the compound of the present invention is useful as a drugcan be evaluated by methods described in various tests and biologicalexamples described hereinafter, and methods which can be carried out byappropriately improving the above methods. The fact that the compound ofthe present invention is kinetically excellent in length of half-life inblood, stability in alimentary canal, oral absorption andbioavailability can be easily evaluated by a known method, for example,a method described in “Drug Bioavailability (Science of Evaluation andImprovement)”, Gendai Iryo-sha, published on Jul. 6, 1998.

In the formula (I) of the present invention, any of each definition byA¹, A², B¹, B², G, E, L, and J is preferred. In the following,preferable groups will be listed. The symbols used herein have the samemeaning as described above.

In the present specification, the “group having a basic group”represented by A¹ and A² is preferably, for example, a“nitrogen-containing heterocyclic ring which may have a substituent(s)”.The “nitrogen-containing heterocyclic ring” in the “nitrogen-containingheterocyclic ring which may have a substituent(s)” here is preferably,for example, imidazole, benzimidazole and pyridine, and the“substituent” is preferably, for example, absent, an aliphatichydrocarbon group, or an aliphatic hydrocarbon group substituted by 1 to5 substituents selected from (5) to (26), (29) to (32) and (37) to (53)in the above T, more preferably, for example, absent, a C1-4 alkylgroup, or an aliphatic hydrocarbon group substituted by an oxo group anda mono- or di-substituted amino group, and still more preferably, forexample, absent, methyl, or a dimethylacetamide group. A¹ and A² arepreferably, for example, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl,and 2-(1H-imidazol-1-yl)-N,N-dimethylacetamide.

In the present specification, the “nitrogen-containing heterocyclicring” in the “nitrogen-containing heterocyclic ring which may have asubstituent(s)” represented by ring A^(1A) and ring A^(2A) ispreferably, for example, imidazole, benzimidazole, or pyridine. Providedthat ring A¹ and ring A² may be the same or different. The “substituent”in the “nitrogen-containing heterocyclic ring which may have asubstituent(s)” represented by ring A^(1A) and ring A^(2A) ispreferably, for example, absent, aliphatic hydrocarbon group, or analiphatic hydrocarbon group substituted by 1 to 5 substituent(s)selected from (5) to (26), (29) to (32) and (37) to (53) in the above T,more preferably, for example, absent, a C1-4 alkyl group (for example,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butylgroup), an aliphatic hydrocarbon group substituted by an oxo group and amono- or di-substituted amino group, and still more preferably, forexample, absent, methyl, or a dimethylacetamide group. Ring A^(1A) andring A^(2A) are preferably, for example, 1H-imidazol-2-yl,1-methyl-1H-imidazol-2-yl, 2-(1H-imidazol-1-yl)-N,N-dimethylacetamide,1-isobutyl-1H-imidazol-2-yl, and 3-methyl-2-pyridinyl, and morepreferably, for example, 1H-imidazol-2-yl or 1-methyl-1H-imidazol-2-yl.

In the present specification, the “substituent” of “imidazole which mayhave a substituent(s), benzimidazole which may have a substituent(s), orpyridine which may have a substituent(s)” represented by ring A^(1B) andring A^(2B) is preferably, for example, absent, an aliphatic hydrocarbongroup, or an aliphatic hydrocarbon group substituted by an oxo group anda mono- or di-substituted amino group and more preferably, for example,absent, a C1-4 alkyl group or N,N-dimethylacetamide.

In the present specification, B¹ and B² each is preferably, for example,a spacer having a main chain of 1 atom and more preferably a methylenegroup (—CH₂—) which may have a substituent(s). The “substituent” hereinis preferably absent or a methyl group and more preferably absent. B¹and B² may be the same or different.

In the present specification, B^(1A) and B^(2A) each is preferably, forexample, —CO—, or —CH₂—. B^(1A) and B^(2A) are more preferably, forexample, —CH₂—.

In the present specification, G is preferably, for example, bond, acarbon atom which may have a substituent(s), an optionally oxidizedsulfur atom, or -(carbon atom which may have a substituent(s))-(nitrogenatom which may have a substituent(s)). The “substituent” here ispreferably, for example, absent, a methyl group, or an oxo group, andmore preferably absent. G is more preferably bond, —CO—, —SO₂—, —CH₂—,or —CONH—. G is still more preferably, for example, bond, —CO—, or—CH₂—.

In the present specification, G¹ is, for example, preferably —CO—,—CH₂—, or the like.

In the present specification, E is preferably, for example, a divalentaliphatic hydrocarbon group having 1 to 4 carbon atom(s) which may havea substituent(s), a divalent 3- to 8-membered monocyclic cyclic groupwhich may have a substituent(s), or a divalent 9- to 10-memberedcondensed cyclic group which may have a substituent(s), more preferably,a divalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s), or a divalent 9- to 10-membered condensed cyclic groupwhich may have a substituent(s). The “divalent 3- to 8-memberedmonocyclic cyclic group which may have a substituent(s)” has the samemeaning as in the above B¹. The “3- to 8-membered monocyclic cyclicring” here is preferably, a C5-7 monocyclic carbocyclic ring (thosehaving 5 to 7 carbon atoms are selected from the above C3-8 monocycliccarbocyclic ring), a 5- to 7-membered monocyclic heterocyclic ring(those having 5- to 7-membered ring are selected from the above 3- to8-membered monocyclic heterocyclic ring), still more preferably, forexample, a cyclopentane, cyclohexane, cycloheptane, cyclohexene,cyclohexadiene, benzene, pyridine, pyrazine, pyrimidine, pyridazine,piperidine, or piperazine ring, and particularly preferably, a benzeneor cyclohexane ring. The “9- to 10-membered condensed cyclic group” inthe “divalent 9- to 10-membered condensed cyclic group which may have asubstituent(s)” is preferably a 9- to 10-membered condensed heterocyclicring, more preferably, for example, a tetrahydroisoquinoline ring. The“substituent” in the “divalent 3- to 8-membered monocyclic cyclic groupwhich may have a substituent(s)” and the “divalent 9- to 10-memberedcondensed cyclic group which may have a substituent(s)” is preferably,for example, absent, a halogen atom, or an aliphatic hydrocarbon group.The “aliphatic hydrocarbon group” herein has the same meaning asdescribed above.

The “divalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s)” is preferably, for example, 1,4-phenylene,1,4-cyclohexylene, 1,3-pyrrolidinediyl, or 1,4-piperidinediyl.

In the present specification, ring E¹ is preferably, for example, adivalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s). The “monocyclic cyclic ring” here is preferably, forexample, cyclopentane, cyclohexane, benzene, pyrrolidine, or piperidinering. The “substituent” here is preferably, absent, an aliphatichydrocarbon group, or a halogen atom. Ring E¹ is preferably, forexample, 1,4-phenylene, 1,4-cyclohexylene, 1,3-pyrrolidinediyl, or1,4-piperidinediyl.

In the present specification, m is preferably, for example, 0 or 1.

In the present specification, L is preferably, for example, a spacerhaving a main chain of 1 to 2 atom(s). The “spacer having a main chainof 1 to 2 atom(s)” here is preferably a divalent group composed of 1 to2 group(s) selected optionally from —O—, —S—, —CO—, —SO—, —SO₂—,divalent nitrogen atom which may have a substituent(s), and a divalentaliphatic hydrocarbon group (methylene) having one carbon atom which mayhave a substituent(s), wherein 1 to 2 atom(s) of the main chain arearranged in a line, more preferably, for example, —CH₂—, —O—CH₂—,—S—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —CH═CH—, —C≡C—, —CH₂—O—, —CH₂—S—,—CH₂—NH—, —CONH—, —SO₂—NH—, —NH—CO—, or —NH—SO₂—, and particularlypreferably, for example, —CH₂—, —CONH—, —CH₂—NH—, —O—CH₂—, —S—CH₂—, or—CH₂—CH₂— (J is bonded to the right side). Also, a bond is alsopreferred. The “substituent” of the divalent nitrogen atom which mayhave a substituent(s)” here is preferably, absent, an aliphatichydrocarbon group, an aliphatic hydrocarbon group substituted by acarboxyl group, an aliphatic hydrocarbon group substituted by a“—COO-aliphatic hydrocarbon group”, an aliphatic hydrocarbon groupsubstituted by a hydroxyl group, an aliphatic hydrocarbon group, or a—CO-cyclic group. The “substituent” of the divalent aliphatichydrocarbon group having one carbon atom which may have asubstituent(s)” is preferably, for example, absent, a methyl group, oran oxo group, more preferably absent.

In the present specification, L^(A) is preferably, for example, adivalent aliphatic hydrocarbon group having 1 to 4 carbon atom(s) whichmay have a substituent(s).

In the present specification, L^(A2) is preferably, for example,-(L^(1B))_(n1)-(in the group, all symbols are as defined above).

In the present specification, J is preferably an aliphatic hydrocarbongroup which is substituted by a basic group, and also may have asubstituent(s), a cyclic group which is substituted by an aliphatichydrocarbon group substituted by a basic group, and also may have asubstituent(s), or an aliphatic hydrocarbon group which is substitutedby a cyclic group substituted by a basic group, and also may have asubstituent(s). The “basic group” here is preferably, for example, amono- or di-substituted amino group, or a nitrogen-containingheterocyclic ring which may have a substituent(s). The “mono- ordi-substituted amino group” here is preferably a di-substituted aminogroup, more preferably, for example, dimethylamino, diethylamino,dipropylamino, dibutylamino, or N-cyclohexyl-N-propylamino, andparticularly preferably, dipropylamino or N-cyclohexyl-N-propylamino.The “nitrogen-containing heterocyclic ring which may have asubstituent(s)” here is preferably, absent, or a nitrogen-containingheterocyclic ring substituted by a C1-8 alkyl group or oxo group, andpreferred “nitrogen-containing heterocyclic ring” includes for example,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydrodiazepine,tetrahydroisoquinoline, 2,8-diazaspiro[4.5]decane,1,4,9-triazaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, or2,9-diazaspiro[5.5]undecane ring.

The “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon groupwhich is substituted by a basic group, and also may have asubstituent(s)” or “aliphatic hydrocarbon group which is substituted bya cyclic group substituted by a basic group, and also which may have asubstituent(s)” is preferably, for example, a C1-8 alkyl group or a C2-8alkenyl group, more preferably, for example, methyl, ethyl, propyl,butyl, pentyl, or hexyl. The “cyclic group” in the “cyclic group whichis substituted by an aliphatic hydrocarbon group substituted by a basicgroup, and also may have a substituent(s)” is preferably, for example, aC5-7 monocyclic carbocyclic ring (those having 5 to 7 carbon atoms areselected from the above C3-15 monocyclic or condensed carbocyclic ring),a 5- to 7-membered monocyclic heterocyclic ring (those having a 5- to7-membered ring are selected from the above 3- to 15-membered monocyclicor condensed heterocyclic ring), more preferably, for example,cyclopentane, cyclohexane, cyclohexene, cyclohexadiene, benzene,pyridine, pyrazine, tetrahydropyran, pyrimidine, pyridazine, piperidine,or piperazine ring. The “substituent” here is preferably, for example,absent, a halogen atom, a methyl group, a hydroxyl group, an aminogroup, or an oxo group, more preferably, absent.

Furthermore, J is preferably, a “cyclic group which is substituted bygroup having a basic group, and also may have a substituent(s)”, a“spiro-bound cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s)”, or a “bridged cyclicgroup which may be substituted with a group having a basic group, andalso may have a substituent(s)”. The “cyclic group”, “spiro-bound cyclicgroup”, or “bridged cyclic group” here is preferably, (1) a spiro-boundcyclic group, (2) a bridged carbocyclic ring, (3) a bridged heterocyclicring composed of a carbon atom(s), an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s), (4) a bridged heterocyclic ringwhich has at least one nitrogen atom, and also may have an oxygenatom(s) and/or an optionally oxidized sulfur atom(s), (5) a C3-15monocyclic or condensed carbocyclic ring, (6) a 3- to 15-memberedmonocyclic or condensed heterocyclic ring composed of a carbon atom(s),an oxygen atom(s) and/or an optionally oxidized sulfur atom(s), or (7) a3- to 15-membered monocyclic or condensed heterocyclic ring which has atleast one nitrogen atom, and also composes of a carbon atom(s), anoxygen atom(s) and/or an optionally oxidized sulfur atom(s).

The “spiro-bound cyclic group” is preferably 2,7-diazaspiro[3.5]nonane,2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane,2,9-diazaspiro[5.5]undecane, 2,8-diazaspiro[5.5]undecane,3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane,1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 8-azaspiro[4.5]decane, 7-azaspiro[4.5]decane,3-azaspiro[5.5]undecane, 2-azaspiro[5.5]undecane,1-oxa-4,8-diazaspiro[5.5]undecane, 1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 2-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 2,3-dihydrospiro[indene-1,4′-piperidine],3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine],3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidine],2-azaspiro[4.5]decane, 2-azaspiro[3.5]nonane,1′,2′-dihydrospiro[cyclohexane-1,3′-indole],2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinoline],1′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-quinoline],1,6-diazaspiro[3.4]octane, 1,5-diazaspiro[3.4]octane,1,7-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.5]nonane,1,5-diazaspiro[3.5]nonane, 1,7-diazaspiro[4.4]nonane,1,6-diazaspiro[4.4]nonane, 1,8-diazaspiro[4.5]decane,1,7-diazaspiro[4.5]decane, 2,6-diazaspiro[3.4]octane,1,6-diazaspiro[4.5]decane, 2,6-diazaspiro[3.5]nonane,1,9-diazaspiro[5.5]undecane, 1,8-diazaspiro[5.5]undecane,6-azaspiro[3.5]nonane, 6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane,1-thia-4,8-diazaspiro[5.5]undecane, spiro[4.4]nonane, spiro[4.5]decane,spiro[5.5]undecane, spiro[3.4]octane, or spiro[3.5]nonane. The“spiro-bound cyclic group” is more preferably 2,7-diazaspiro[3.5]nonane,2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane,2,9-diazaspiro[5.5]undecane, 2,8-diazaspiro[5.5]undecane,3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane,1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 1-oxa-4,8-diazaspiro[5.5]undecane,1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 1,6-diazaspiro[3.4]octane,1,5-diazaspiro[3.4]octane, 1,7-diazaspiro[3.5]nonane,1,6-diazaspiro[3.5]nonane, 1,5-diazaspiro[3.5]nonane,1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[4.4]nonane,1,8-diazaspiro[4.5]decane, 1,7-diazaspiro[4.5]decane,2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[4.5]decane,2,6-diazaspiro[3.5]nonane, 1,9-diazaspiro[5.5]undecane,1,8-diazaspiro[5.5]undecane, 1,7-diazaspiro[5.5]undecane,1,4,9-triazaspiro[5.5]undecane, 1,3,8-triazaspiro[4.5]decane,1-thia-4,9-diazaspiro[5.5]undecane, or1-thia-4,8-diazaspiro[5.5]undecane. The “spiro-bound cyclic group” isparticularly preferably 2,7-diazaspiro[4.5]decane,2,8-diazaspiro[4.5]decane, 2,8-diazaspiro[5.5]undecane,2,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, or1-oxa-4,9-diazaspiro[5.5]undecane. The most preferable “spiro-boundcyclic group” is a 2,8-diazaspiro[4.5]decane ring.

The “bridged carbocyclic ring” is preferably bicyclo[2.1.1]hexane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane,adamantane, bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane, orbicyclo[3.3.2]decane.

The “bridged heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s)” is preferablyoxabicyclo[2.2.1]heptane or oxabicyclo[3.2.1]octane.

The “bridged heterocyclic ring which has at least one nitrogen atom, andalso may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s)” is preferably 1-azatricyclo[3.3.1.1^(3,7)]decane,3-azabicyclo[3.3.1]nonane, or 3,7-diazabicyclo[3.3.1]nonane.

The “C3-15 monocyclic or condensed carbocyclic ring” is preferablycyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene,perhydroindene, indane, naphthalene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, or1,2,3,5,6,7-hexahydro-s-indacene. More preferably, it is cyclopentane,cyclohexane, or cyclooctane. Most preferably, it is cyclohexane.

The “3- to 15-membered monocyclic or condensed heterocyclic ringcomposed of a carbon atom, an oxygen atom and/or an optionally oxidizedsulfur atom” is preferably a partially or completely saturated 3- to15-membered monocyclic or condensed heterocyclic ring composed of acarbon atom(s), an oxygen atom(s) and/or an optionally oxidized sulfuratom(s).

The “3- to 15-membered monocyclic or condensed heterocyclic ring whichhas at least one nitrogen atom, and also composes of a carbon atom(s),an oxygen atom(s) and/or an optionally oxidized sulfur atom(s)” ispreferably a partially or completely saturated 3- to 15-memberedmonocyclic or condensed heterocyclic ring which has at least onenitrogen atom, and also composes of a carbon atom(s), an oxygen atom(s)and/or an optionally oxidized sulfur atom(s).

The “7- to 15-membered spiro-bound bicyclic heterocyclic ring whichconsists of a monocyclic cyclic ring composed of (i) at least onenitrogen atom, and/or a monocyclic cyclic ring composed of (ii) at leastone nitrogen atom, one oxygen atom and carbon atoms” among the“spiro-bound heterocyclic ring” is preferably is a monocyclic cyclicring wherein the ring constituting the spiro-bound heterocyclic ring isa monocyclic cyclic ring composed of at least one nitrogen atom and acarbon atom and/or a 9- to 11-membered spiro-bound bicyclic heterocyclicring composed of at least one nitrogen atom, one oxygen atom and carbonatoms.

The 9- to 11-membered spiro-bound bicyclic heterocyclic ring whichconsists of a monocycle composed of at least one nitrogen atom and acarbon atom and/or a monocyclic cyclic ring composed of at least onenitrogen atom, one oxygen atom and carbon atoms” is preferably,2,7-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane,2,8-diazaspiro[5.5]undecane, 2,9-diazaspiro[5.5]undecane,2,7-diazaspiro[3.5]nonane, or 1-oxa-4,9-diazaspiro[5.5]undecane ring.

The “substituent” of “may have 1 to 8 substituent(s)” or “may have asubstituent(s)” of ring J¹, ring J², ring J³, ring J⁴, and J⁵ ispreferably, for example, an aliphatic hydrocarbon group, a cyclic group,or an aliphatic hydrocarbon group substituted by a cyclic group, morepreferably a C1-8 aliphatic hydrocarbon group, or a C3-10 monocyclic orbicyclic carbocyclic ring. Absent is also preferred as the “substituent”of “optionally substituted by the substituent” of ring J¹.

The “substituent” of “optionally substituted by the substituent” of ringJ² is preferably, for example, an aliphatic hydrocarbon group or acyclic group, more preferably, for example, C1-8 alkyl group,cyclopentane, cyclohexane, cycloheptane, or benzene ring.

In the present specification, the “substituent” of “o may have 1 to 8substituent(s) on the substitutable position” of ring J^(1a), ringJ^(1b), and ring J^(2a)” is preferably, for example, absent, a halogenatom, or an aliphatic hydrocarbon group, and more preferably absent.

In the present specification, the “substituent” of “may have 1 to 8substituent(s) on the substitutable position” of ring J^(2b) ispreferably, for example, C1-8 alkyl group, cyclopentane, cyclohexane,cycloheptane, or benzene ring.

The “group having a basic group” of “substituted with a group having abasic group” or “may be substituted with a group having a basic group”of ring J², ring J³, ring J⁴, and J⁵ is preferably, for example, a mono-or di-substituted amino group, or a nitrogen-containing heterocyclicring which may have a substituent(s). The “mono- or di-substituted aminogroup” here is preferably a di-substituted amino group, more preferably,for example, dimethylamino, diethylamino, dipropylamino, dibutylamino,or N-cyclohexyl-N-propylamino, and particularly preferably,dipropylamino or N-cyclohexyl-N-propylamino. The “nitrogen-containingheterocyclic ring which may have a substituent(s)” here is preferably apiperidine ring. The substituent of the “mono-substituted amino group”of the “mono- or di-substituted amino group” is preferably cyclohexaneor cycloheptane ring.

In the present specification,

is preferably, -(L^(B1))_(n1)-J^(B) (in the group, all symbols are asdefined above).

In the present specification, J^(B) is preferably, for example,

(in the group, the arrow is bonded to L^(1B), and R¹ is as definedabove).

In the present specification, a compound of formula (I) including acombination of preferable groups listed above is preferable.

In the present specification, the preferred compound includes compoundsrepresented by formula (I-1):

wherein all symbols are as defined above,formula (I-2):

wherein all symbols are as defined above,formula (I-3):

wherein all symbols are as defined above, andformula (I-4):

wherein all symbols are as defined above,a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof.

In the present specification, more preferred compound includes compoundsrepresented by formula (I-5):

(wherein ring E² represents a monocyclic carbocyclic ring which may havea substituent(s), and other symbols are as defined above), formula(I-6):

(wherein ring E³ represents a divalent monocyclic heterocyclic ringwhich may have a substituent(s), ring J⁶ represents a monocyclic orcondensed heterocyclic ring which may have a substituent(s), and othersymbols are as defined above), andformula (I-7):

(wherein G² represents a bond or —CH₂—, and other symbols are as definedabove), a salt thereof, or an N-oxide thereof, or a solvate thereof, ora prodrug thereof.

In the present invention, more preferred compounds are compoundsrepresented by formula (I-2-a):

(wherein all symbols are as defined above),formula (I-2-b)

(wherein all symbols are as defined above),formula (I-2-c):

(wherein all symbols are as defined above) andformula (I-4-a):

(wherein all symbols are as defined above),a salt thereof, or an N-oxide thereof, or a solvate thereof, or aprodrug thereof.

In the present specification, the “monocyclic carbocyclic ring which mayhave a substituent(s)” represented by ring E² has the same meaning asthose wherein the “3- to 8-membered monocyclic cyclic ring” is a “C3-8monocyclic carbocyclic ring” among divalent groups which can be obtainedby eliminating optional two hydrogen atoms from the “3- to 8-memberedmonocyclic cyclic ring” in the “divalent 3- to 8-membered monocycliccyclic group which may have a substituent(s)”. The “C3-8 monocycliccarbocyclic ring” here is preferably benzene or cyclohexane.

In the present specification, the “monocyclic carbocyclic ring which mayhave a substituent(s)” represented by ring E³ has the same meaning asthose wherein the “3- to 8-membered monocyclic cyclic ring” is a “3- to8-membered monocyclic heterocyclic ring” among divalent groups which canbe obtained by eliminating optional two hydrogen atoms from the “3- to8-membered monocyclic cyclic ring” in the “divalent 3- to 8-memberedmonocyclic cyclic group which may have a substituent(s)”. The “3- to8-membered monocyclic heterocyclic ring” here is preferably piperidine.

In the present specification, the “substituent” of ring E² and ring E³is not specifically limited. Examples of the “substituent” include thoseexemplified as for T, and these optional substituents may be substitutedon the substitutable position and the number of substituents may be from1 to 6, and preferably from 1 to 3. The “substituent” of ring E² andring E³ is preferably, for example, absent, a halogen atom, or analiphatic hydrocarbon group.

In the present specification, ring E² is preferably, for example, acyclopentane which may have a substituent(s), a cyclohexane which mayhave a substituent(s), or a benzene ring which may have asubstituent(s). The “substituent” here is preferably, for example, analiphatic hydrocarbon group or a halogen atom.

In the present specification, ring E³ is preferably, for example,pyrrolidine, piperidine, pyrrolidine substituted by a C1-4 alkyl group,or a piperidine ring substituted by a C1-4 alkyl group.

In the present specification, the “monocyclic or condensed heterocyclicring” in the “monocyclic or condensed heterocyclic ring which may have asubstituent” represented by ring J⁶ has the same meaning as the“monocyclic or condensed heterocyclic ring”. The “substituent” of ringJ⁶ is not specifically limited. Examples of the “substituent” includethose exemplified as for T, and these optional substituents may besubstituted on the substitutable position and the number of substituentsmay be from 1 to 8, and preferably from 1 to 5.

The substituent of ring J^(2b) is preferably R¹.

R¹ is preferably, an aliphatic hydrocarbon group which may have asubstituent(s), an aliphatic hydrocarbon group substituted by a cyclicgroup which may have a substituent(s), or a cyclic group which may havea substituent(s). The “aliphatic hydrocarbon group” of the “an aliphatichydrocarbon group which may have a substituent(s)” and the “aliphatichydrocarbon group substituted by a cyclic group which may have asubstituent(s)” represented by R¹ is preferably, a C1-8 alkyl group,more preferably, for example, sec-butyl, tert-butyl, or pentyl. The“cyclic group” of the “cyclic group which may have a substituent(s)”represented by R¹ is preferably, a C3-15 monocyclic or condensedunsaturated carbocyclic ring, or a partially or completely saturatedcarbocyclic ring, more preferably a C3-8 monocyclic saturatedcarbocyclic ring, and particularly preferably a cyclopropane,cyclobutane, cyclopentane, cyclohexane, or cycloheptane ring. The“substituent” of the “aliphatic hydrocarbon group which may have asubstituent(s)” is preferably a cyclopentane, cyclohexane, thiophene, ora benzene ring. The “cyclic group” of the “aliphatic hydrocarbon groupsubstituted by a cyclic group which may have a substituent(s)” ispreferably a thiophene ring.

Preferred compound of the present invention include compounds describedin Examples, a salt thereof, or an N-oxide thereof, or a solvatethereof, or a prodrug thereof.

[Method for Producing Compound of the Present Invention]

The compound of the present invention represented by formula (I) can beprepared by appropriately improving a known method, for example, methodsshown below, methods described in Examples, and a method described inComprehensive Organic Transformations: A Guide to Functional GroupPreparations, Second edition (written by Richard C. Larch, John Wiley &Sons Inc, 1999) and using improved methods in combination. In thefollowing production methods, starting compounds may be used in the formof a salt. As the salt, those described as a salt of the above describedformula (I) are used.

A compound wherein G represents —CO— among the compounds of the presentinvention represented by formula (I), namely, a compound represented byformula (I-A):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by formula (2):

(wherein all symbols are as defined above) and a compound represented byformula (3):

(wherein W represents a hydroxyl group or a chlorine atom, and othersymbols are as defined above) to the amidation reaction, and optionallysubjecting to the deprotection reaction of the protective group and/orthe cleavage reaction from the resin.

This amidation reaction is known and examples thereof include:

(1) a method using an acyl halide,

(2) a method using a mixed acid anhydride, and

(3) a method using a condensing agent.

These methods are described in detail below.

(1) The method using an acyl halide is carried out, for example, byreacting carboxylic acid with an acid halogenating agent (oxalylchloride, thionyl chloride, etc.) in an organic solvent (chloroform,dichloromethane, diethylether, tetrahydrofuran, etc.) or in the absenceof the solvent at −20° C. to reflux temperature. Then the obtained acylhalide derivative may be with amine in the presence of a base (pyridine,triethylamine, N,N-dimethylaniline, 4-dimethylaminopyridine,diisopropylethylamine, etc.) in an organic solvent (chloroform,dichloromethane, diethylether, tetrahydrofuran, etc.) at 0 to 40° C.Alternatively, the obtained acyl halide can be reacted with amine in anorganic solvent (dioxane, tetrahydrofuran, etc.) at 0 to 40° C. using anaqueous alkali solution (sodium bicarbonate water or sodium hydroxidesolution, etc.).

(2) The method using a mixed acid anhydride is carried out, for example,by reacting carboxylic acid with an acyl halide (pivaloyl chloride,tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethylchloroformate, butyl chloroformate, etc.) in the presence of a base(pyridine, triethylamine, N,N-dimethylaniline, 4-dimethylaminopyridine,diisopropylethylamine, etc.) in an organic solvent (chloroform,dichloromethane, diethylether, tetrahydrofuran, etc.) or in the absenceof the solvent at 0 to 40° C., and reacting the resulting mixed acidanhydride with amine in an organic solvent (chloroform, dichloromethane,diethylether, tetrahydrofuran, etc.) at 0 to 40° C.

(3) The method using a condensing agent is carried out, for example, byreacting carboxylic acid with amine in an organic solvent (chloroform,dichloromethane, dimethyl formamide, diethylether, tetrahydrofuran,etc.) or in the absence of the solvent at 0 to 40° C. in the presence orabsence of a base (pyridine, triethylamine, diisopropylethylamine,N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, etc.),using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI),O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 2-chloro-1-methylpyridiniumiodine,1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acidcyclic anhydride, PPA), etc.) and using, or not using,1-hydroxybenztriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt).

The reactions described in (1), (2) and (3) are preferably carried outunder an inert gas (argon, nitrogen, etc.) atmosphere on anhydrouscondition.

The deprotection reaction of a protective group can be carried out by aknown method, for example, a method described in Protective Groups inOrganic Synthesis (written by T. W. Greene, John Wiley & Sons Inc,1999).

If the compound has a moiety to bind to a resin in the molecule and theresin is a polystyrene resin, the compound of the present invention canbe cleaved from the resin by the following method. The reaction forcleavage from the resin is known and can be carried out, for example, byreacting in an organic solvent (dichloromethane, 1,2-dichloroethane,toluene, etc.) at 0 to 100° C. using an acid (acetic acid,trifluoroacetic acid, hydrochloric acid, etc.).

If necessary, the procedure of converting into the objective salt may becarried out by a known method after this reaction.

A compound wherein G represents —SO₂— among the compounds of the presentinvention represented by formula (I), namely, a compound represented byformula (I-B):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by formula (2) and a compound represented byformula (4):

(wherein X represents a halogen atom, and other symbols are as definedabove) to the sulfonamidation reaction, and optionally subjecting to thedeprotection reaction of the protective group and/or the cleavagereaction from the resin.

The sulfonamidation reaction is known and can be carried out by thefollowing method. For example, a sulfonyl halide can be synthesized byreacting a sulfonic acid with an acyl halide (oxalyl chloride, thionylchloride, phosphorous pentachloride, phosphorus trichloride orphosphorus oxychloride, or a mixture thereof, etc.) in an organicsolvent (chloroform, dichloromethane, dichloroethane, diethylether,tetrahydrofuran, methyl t-butyl ether, etc.) or in the absence of thesolvent at −20° C. to reflux temperature in the presence or absence ofdimethyl formamide, or reacting a thiol with a chlorine gas in anaqueous acid solution (for example, hydrochloric acid, sulfuric acid,nitric acid, acetic acid, etc.) at 0° C. to reflux temperature. Thesulfonyl halide thus synthesized can be reacted with amine in thepresence of a base (diisopropylethylamine, pyridine, triethylamine,N,N-dimethylaniline, 4-dimethylaminopyridine, etc.) in an organicsolvent (chloroform, dichloromethane, dichloroethane, diethylether,tetrahydrofuran, etc.) at 0 to 40° C. The deprotection reaction of aprotective group or the cleavage reaction from the resin can be carriedout by the same method as described above.

A compound wherein G represents -(a carbon atom substituted by an oxogroup)-NH— among the compound of the present invention represented byformula (I), namely, a compound represented by formula (I-N):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by general formula (2), a phosgene equivalent(phosgene, diphosgene, triphosgene, carbonyldiimidazole, etc.) and acompound represented by formula (28):H₂N-E-L-J  (28)(wherein all symbols are as defined above) to the urea reaction, andoptionally subjecting to the deprotection reaction of the protectivegroup and/or the cleavage reaction from the resin.

This urea reaction is known and is conducted, for example, by reacting acompound represented by formula (2) with a phosgene derivative(phosgene, diphosgene, triphosgene, carbonyldiimidazole, etc.) at −78°C. to 40° C. in an organic solvent (dichloromethane, chloroform,diethylether, tetrahydrofuran, etc.) or in the absence of the solvent inthe presence of a base (pyridine, triethylamine,N,N-diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine,etc.). Furthermore, the reaction is conducted by reacting the resultingcompound with a compound represented by formula (28) at −78° C. to 40°C. in an organic solvent (dichloromethane, chloroform, diethylether,tetrahydrofuran, etc.) or in the absence of the solvent in the presenceof a base (pyridine, triethylamine, N,N-diisopropylethylamine,4-dimethylaminopyridine, N-methylmorpholine, etc.).

This reaction is preferably performed in an inert gas (argon, nitrogen,etc.) atmosphere under anhydrous conditions.

The deprotection reaction of a protective group or the cleavage reactionfrom the resin can be carried out by the same method as described above.

If necessary, this reaction may be followed by an operation ofconverting into the objective salt by using a known method.

A compound wherein L represents an amide bond among the compounds of thepresent invention represented by formula (I), namely, a compoundrepresented by formula (I-C-1):

(wherein R^(C1) represents a hydrogen atom, or a substituent or ahydrogen atom in a “divalent nitrogen atom which may have asubstituent(s)” defined in L. and other symbols are as defined above) ora compound represented by formula (I-C-2):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by formula (5):

(wherein all symbols are as defined above) and a compound represented byformula (6):

(wherein all symbols are as defined above) to the amidation reaction,and optionally subjecting to the deprotection reaction of the protectivegroup and/or the cleavage reaction from the resin, or subjecting acompound represented by formula (7):

(wherein all symbols are as defined above) and a compound represented byformula (8):

(wherein all symbols are as defined above) to the amidation reaction,and optionally subjecting to the deprotection reaction of the protectivegroup and/or the cleavage reaction from the resin.

The amidation reaction, the deprotection reaction of a protective group,or the cleavage reaction from the resin can be carried out by the samemethod as described above.

A compound wherein L represents a sulfonamide bond among the compoundsof the present invention represented by formula (I), namely, a compoundrepresented by formula (I-D-1):

(wherein all symbols are as defined above) or a compound represented byformula (I-D-2):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by formula (5) and a compound represented byformula (9):

(wherein all symbols are as defined above) to the sulfonamidationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin, orsubjecting a compound represented by formula (7) and a compoundrepresented by formula (10):

(wherein all symbols are as defined above) to the sulfonamidationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin.

The sulfonamidation reaction, the deprotection reaction of a protectivegroup, or the cleavage reaction from the resin can be carried out by thesame method as described above.

A compound wherein L represents an optionally substituted—CH(—R^(E1))—NH— or —NH—CH(—R^(E1))— (in the group, R^(E1) has the samemeaning as the substituent of “a divalent aliphatic hydrocarbon grouphaving 1 to 4 carbon atom(s) which may have a substituent(s)” in ahydrogen atom or L among the compounds of the present inventionrepresented by formula (I), namely, a compound represented by formula(I-E-1):

(wherein all symbols are as defined above) or a compound represented byformula (I-E-2):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by formula (11):

(wherein all symbols are as defined above) and a compound represented byformula (12):

(wherein all symbols are as defined above) to the reductive aminationreaction, or optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin, orsubjecting a compound represented by formula (13):H₂N-J  (13)(wherein all symbols are as defined above) and a compound represented byformula (14):

(wherein all symbols are as defined above) to the reductive aminationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin.

This reductive amination reaction is known and is carried out, forexample, in an organic solvent (dichloroethane, dichloromethane,dimethyl formamide, acetic acid, a mixture thereof, etc.) at 0 to 40° C.in the presence of a reducing agent (sodium triacetoxyborohydride,sodium cyanoborohydride, sodium borohydride, etc.). The deprotectionreaction of a protective group or the cleavage reaction from the resincan be carried out by the same method as described above.

A compound wherein a basic group in a J group is a mono-substitutedamino group among the compounds of the present invention represented byformula (I), namely, a compound represented by formula (I-F):

(wherein J^(F) represents a divalent aliphatic hydrocarbon group whichmay have a substituent(s), a divalent cyclic group which may have asubstituent(s), a divalent aliphatic hydrocarbon group substituted witha cyclic group which may have a substituent(s), a divalent cyclic groupsubstituted with an aliphatic hydrocarbon group which may have asubstituent(s), a divalent spirocyclic group which may have asubstituent(s), or a divalent bridged cyclic group which may have asubstituent(s), R^(F1) represents a substituent in a substituent bondedto an amino group via CH₂ among a “mono-substituted amino group” definedin J, and other symbols are as defined above) can be prepared, forexample, by subjecting the compound prepared by the above method, namelya compound represented by formula (I-F-1):

(wherein all symbols are as defined above) and a compound represented byformula (15):R¹—CHO  (15)(wherein all symbols are as defined above) to the reductive aminationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin.

The reductive amination reaction, the deprotection reaction of aprotective group, or the cleavage reaction from the resin can be carriedout by the same method as described above.

A compound wherein a basic group in a J group is a di-substituted aminogroup among the compounds of the present invention represented byformula (I), namely, a compound represented by formula (I-G):

(wherein R^(F2) represents a substituent in a substituent bonded to anamino group via CH₂ among substituents in a “di-substituted amino group”defined in J, and other symbols are as defined above) can be prepared bythe compound prepared by the above method, namely, a compoundrepresented by formula (I-F) and a compound represented by formula (16):R^(F2)—CHO  (16)(wherein all symbols are as defined above) to the reductive aminationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin.

The reductive amination reaction, the deprotection reaction of aprotective group, or the cleavage reaction from the resin can be carriedout by the same method as described above.

A compound wherein R^(F1) and R^(F2) represent the same substituentamong the compounds of the present invention represented by formula(I-G) can be prepared by subjecting a compound represented by formula(I-F-1) and two or more equivalents of a compound represented by formula(15) or formula (16) to the reductive amination reaction, and optionallysubjecting to the deprotection reaction of the protective group and/orthe cleavage reaction from the resin.

The reductive amination reaction, the deprotection reaction of theprotective group, or the cleavage reaction from the resin can beconducted by the same method as described above.

A compound wherein A¹ and A² represent an imidazol-2-yl group among thecompound of the present invention represented by formula (I), namely, acompound represented by formula (I-H):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by formula (17):

(wherein all symbols are as defined above) and[2,2-bis(methyloxy)ethyl]amine or[2,2-bis(ethyloxy)ethyl]amine to thecyclization reaction, and optionally subjecting to the deprotectionreaction of the protective group and/or the cleavage reaction from theresin.

This cyclization reaction is known and can be performed, for example, byimproving the method described in Synthesis, 2001, (10), 1546-1550. Forexample, it is performed by reacting a nitrile compound in an organicsolvent (methanol, ethanol, etc.) in the presence of a base (sodiummethoxide, sodium ethoxide, etc.) at 0 to 40° C. and reacting thesolution in the presence of acetal and a dehydrating agent (glacialacetic acid) at 40 to 150° C. Also, a deprotection reaction of aprotective group or a cleavage reaction from a resin can be performed bythe same method as described above.

A compound wherein a divalent group adjacent to a nitrogen atom is adivalent group in B¹ among the compounds of the present inventionrepresented by formula (I), namely, a compound represented by formula(I-K):

(wherein B^(1K) represents a bond or a spacer having a main chain of 1to 3 atom(s), and other symbols are as defined above) can be prepared bysubjecting a compound represented by formula (20):A²-B²—NH-G-E-L-J  (20)(wherein all symbols are as defined above) and a compound represented byformula (21):

(wherein all symbols are as defined above) to the amidation reaction,and optionally subjecting to the deprotection reaction of the protectivegroup and/or the cleavage reaction from the resin.

The amidation reaction, the deprotection reaction of a protective group,or the cleavage reaction from the resin can be carried out by the samemethod as described above.

A compound wherein a divalent group adjacent to a nitrogen atom is —SO₂—in B¹ among the compounds of the present invention of formula (I),namely, a compound represented by formula (I-L):

(wherein B^(1L) represents a bond or a spacer having a main chain of 1to 3 atom(s), and other symbols are as defined above) can be prepared bysubjecting a compound represented by formula (20) and a compoundrepresented by formula (22):

(wherein all symbols are as defined above) to the sulfonamidationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin.

The sulfonamidation reaction, the deprotection reaction of a protectivegroup, or the cleavage reaction from the resin can be carried out by thesame method as described above.

A compound wherein G represents one carbon atom which may have asubstituent(s) and a divalent group adjacent to a nitrogen atom is —CH₂—in B¹ and B² among the compounds represented by formula (I), namely, acompound represented by formula (I-M):

(wherein B^(1K) and B^(2K) each independently represents a bond or aspacer having a main chain of 1 to 3 atom(s), R^(M1) represents ahydrogen atom or a substituent in a “carbon atom which may have asubstituent(s)” defined in G, and other symbols are as defined above)can be prepared by subjecting a compound represented by formula (23):

(wherein all symbols are as defined above) and a compound represented byformula (24):

(wherein all symbols are as defined above) to the reductive aminationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin.

The reductive amination reaction, the deprotection reaction of aprotective group, or the cleavage reaction from the resin can be carriedout by the same method as described above.

A compound represented by formula (I-M) can be prepared by subjecting acompound represented by formula (25):

(wherein all symbols are as defined above) and a compound represented byformula (26):A¹-B^(1K)—CHO  (26)(wherein all symbols are as defined above) to the reductive aminationreaction, subjecting the resulting compound and a compound representedby formula (27):A²-B^(2K)—CHO  (27)(wherein all symbols are as defined above) to the reductive aminationreaction, and optionally subjecting to the deprotection reaction of theprotective group and/or the cleavage reaction from the resin.

The reductive amination reaction, the deprotection reaction of aprotective group, or the cleavage reaction from the resin can be carriedout by the same method as described above.

A compound wherein an A¹-B^(1K)—CH₂ group and an A²-B^(2K)—CH₂ grouprepresent the same substituent among the compounds of the presentinvention represented by formula (I-M) can be prepared by subjecting acompound represented by formula (25) and two or more equivalents of acompound represented by formula (26) or compound represented by formula(27) to the reductive amination reaction, and optionally subjecting tothe deprotection reaction of the protective group and/or the cleavagereaction from the resin.

The reductive amination reaction, the deprotection reaction of aprotective group, or the cleavage reaction from the resin can be carriedout by the same method as described above.

A compound wherein G is bond among the compounds represented by formula(I), namely, a compound represented by formula (I-P):

(wherein all symbols are as defined above) can be prepared by subjectinga compound represented by formula (26) and a compound represented byformula (28) to the reductive amination reaction, subjecting a resultingcompound and a compound represented by formula (27) to the reductiveamination reaction, and optionally subjecting to the deprotectionreaction of the protective group and/or the cleavage reaction from theresin.

The reductive amination reaction, the deprotection reaction of aprotective group, or the cleavage reaction from the resin can be carriedout by the same method as described above.

A compound wherein an A¹-B^(1K)—CH₂ group and an A²-B^(2K)—CH₂ grouprepresent the same substituent among the compounds of the presentinvention represented by formula (I-P) can be prepared by subjecting acompound represented by formula (28) and two or more equivalents of acompound represented by formula (26) or a compound represented byformula (27) to the reductive amination reaction, and optionallysubjecting to the deprotection reaction of the protective group and/orthe cleavage reaction from the resin.

The compounds represented by formulas (2) to (28) used as other startingmaterials or reagents can be easily prepared by using per se knownmethods or known methods, for example, methods described inComprehensive Organic Transformations: A Guide to Functional GroupPreparations, Second edition (written by Richard C. Larch, John Wiley &Sons Inc, 1999) in combination.

In the respective reactions in the present specification, as is apparentto those skilled in the art, the reaction with heating can be carriedout using a water bath, an oil bath, a sand bath, or microwave.

In the respective reactions in the present specification, a solid phasesupported reagent obtained by supporting on a polymer (for example,polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.)may be used.

In the respective reactions in the present specification, the reactionproduct can be purified by conventional purification means, for example,distillation under normal pressure or reduced pressure, high performanceliquid chromatography using a silica gel or magnesium silicate, thinlayer chromatography, ion-exchange resin, scavenger resin orchromatography or washing, or recrystallization. The purification may becarried out for every reaction, or may be carried out after thecompletion of some reactions.

In the reaction using a polystyrene resin in the present specification,the reaction product can be purified by conventional purificationmethods, for example, washing plural times with a solvent (N,N-dimethylformamide, dichloromethane, methanol, tetrahydrofuran, toluene, aceticacid/toluene, etc.).

[Toxicity]

The compound of the present invention has very low toxicity and issufficiently safe for use as pharmaceuticals.

[Application to Pharmaceuticals]

The compound of the present invention has CXCR4 antagonistic activity inan animal including human, particularly human, and is thereforeeffective, for example, for a preventive and/or therapeutic agent forinflammatory and immune diseases, allergic diseases, infections,particularly HIV infection, and diseases associated with the infection,psychoneurotic diseases, cerebral diseases, cardiovascular diseases,metabolic diseases, and cancerous diseases. Also, the compound is usefulas an agent for regeneration therapy for the purpose of in vitro or invivo amplification of stem cells for gene therapy as well as peripheralblood stem cells mobilization and tissue repair. The compound isparticularly useful as an agent for transplantation medical treatmentused in organ transplantation including bone marrow transplantation,peripheral blood stem cell transplantation and tissue repair among inthe regeneration therapy. Furthermore, the compound is useful as anantiangiogenic agent which is effective for prevention and/or treatmentof diseases associated with neoangiogenesis, such as retinopathy(diabetic retinopathy, aged macular degeneration, glaucoma, etc.) andcancer proliferation.

Examples of the inflammatory and immune disease include rheumatoidarthritis, arthritis, retinopathy, systemic erythematosus, gout,rejection of transplanted organ, graft-versus-host disease (GVHD),nephritis, psoriasis, rhinitis, conjunctivitis, multiple sclerosis,ulcerative colitis, Crohn's disease, shock associated with bacterialinfection, pulmonary fibrosis, systemic inflammatory response syndrome(SIRS), acute lung injury, diabetes and the like.

Examples of the allergic disease include asthma, atopic dermatitis,rhinitis, conjunctivitis and the like.

Examples of infections include, for example, HIV infection, variousinfections caused by streptococcus (Group A β-hemolytic streptococcus,Streptococcus pneumoniae, etc.), staphylococcus aureus (MSSA, MRSA),Staphylococcus epidermidis, enterococcus, Listeria, meningococcus,gonococcus, E. coli bacteria (0157:H7, etc.), klebsiella (Klebsiellapneumoniae), Proteus, tussis convulsiva, Pseudomonas aeruginosa,Serratia marcescens, shitorobactar, Ashinetobactar, Enterobactar,mycoplasma, chlamydia, and Crostorigeum, cholera, diphtheria, dysentery,scarlet fever, anthrax, trachoma, syphilis, tetanus, Hansen's disease,legionella, Reptospira, Lyme disease, tularaemia, Q fever, meningitis,encephalitis, rhinitis, sinusitis, pharyngitis, laryngitis, orbitalcellulitis, thyroiditis, Lemierre syndrome, pneumonia, bronchitis,tuberculosis, infectious endocarditis, pericarditis, myocarditis,infectious aortitis, septicemia, cholecystitis, cholangitis, hepatitis,liver abscess, acute pancreatitis, splenic abscess, enteritis, iliopsoasabscess, pyelonephritis, cystitis, prostatitis, colpitis, Pelvicinflammatory disease, cellulitis, panniculitis, gas gangrene, furuncle,carbuncle, contagious impetigo, staphylococcal scalded skin syndrome,herpes zoster, varicella, measles, rubella, impetigo, scabies,infectious arthritis, osteomyelitis, fasciitis, myositis, andlymphadenitis.

Examples of the disease associated with infection, particularly HIVinfection, include acquired immunodeficiency syndrome (AIDS),candidiasis, Pneumocystis carinii pneumonia, Cytomegalovirus retinitis,Kaposi's sarcoma, malignant lymphoma, AIDS encephalopathy, bacterialsepsis and the like.

Examples of the psychoneurotic disease and cerebral disease includedementia including Alzheimer's disease, Parkinson's disease, stroke,cerebral infarction, cerebral hemorrhage, epilepsia, schizophrenia,peripheral nerve disorder and the like.

Examples of the cardiovascular disease include arteriosclerosis,ischemia reperfusion, hypertension, myocardial infarction, stenocardia,heart failure, chronic arterial occlusive disease and the like.

Examples of the metabolic diseases include diabetes, osteoporosis,enlarged prostate, frequent micturition and the like.

Macular degeneration is a disease wherein progressive disorder arises inmacula lutea that is present in the center of retina and controls visualacuity, and age-related one is referred to as age-related maculardegeneration. Macular degeneration includes atrophy type (dry type)macular degeneration wherein macula lutea tissue causes atrophy andexudation type (wet type) macular degeneration wherein new blood vesselare formed in the chorioidea of the macula lutea site.

Examples of the cancerous disease include malignant tumor such as breastcancer or malignant lymphoma, cancer metastasis, myelosuppression orthrombocytopenia after radiation therapy/chemotherapy and the like.

The compound of the present invention may be administered as aconcomitant drug by using in combination with other drugs for thepurpose of:

1) complementation and/or enhancement of the preventive and/ortherapeutic effects of the compound,

2) improvement of pharmacokinetics and absorption of the compound andreduction of the dosage, and/or

3) reduction of side effects of the compound.

Also, the compound of the present invention may be administered as aconcomitant drug by using in combination with other drugs the purpose of(1) complementation and/or enhancement of preventive and/or therapeuticeffects, (2) improvement of pharmacokinetics and absorption of thecompound and reduction of the dosage, and/or (3) reduction of sideeffects.

The concomitant drug of the compound of the present invention and otherdrugs may be administered in the form of a compounding agent(s)comprising both these components, or may be in the form of separately.In case of separately administering a preparation, simultaneousadministration and administration with time-lag are included. In case ofadministration with time-lag, other drugs may be administered after thecompound of the present invention is administered, or the compound ofthe present invention may be administered after other drugs may beadministered. The administration method may be the same or different.

The disease, on which the preventive and/or therapeutic effects areexerted by the concomitant drug, is not specifically limited, and may beany disease which complements and/or enhances the preventive and/ortherapeutic effects of the compound of the present invention.

A mass ratio of the compound of the present invention drug to otherdrugs is not specifically limited.

A combination of any two or more kinds other drugs may be administered.

The other drugs, which complements and/or enhances the preventive and/ortherapeutic effects of the compound of the present invention, includesnot only those which have ever been found based on the above describedmechanism, but also those which may be found in future.

Examples of the preventive and/or therapeutic agents for HIV infectionand acquired immunodeficiency syndrome, which is used in combination ofthe compound of the present invention, include reverse transcriptaseinhibitors, protease inhibitors, chemokine (for example, CCR2, CCR3,CCR4, CCR5, CXCR4, etc.) antagonists, CD4 antagonists, antibody againstsurface antigen of HIV (for example, HIV-1, HIV-2, etc.), vaccine of HIV(for example, HIV-1, HIV-2, etc.), short-interfering RNAs targeting aHIV-related factor and the like.

Examples of the reverse transcriptase inhibitors include (1) nucleosidereverse transcriptase inhibitors such as zidovudine (trade name:Retrovir), didanosine (trade name: Videx), zalcitabine (trade name:Hivid), stavudine (trade name: Zerit), lamivudine (trade name: Epivir),abacavir (trade name: Ziagen), didanosine (trade name: videx), adefovir,dipivoxil, emtricitabine (trade name: coviracil), tenofovir (trade name:viread), Combivir, Trizivir, truvada, epzicom, and the like, (2)non-nucleoside reverse transcriptase inhibitors such as nevirapine(trade name: viramune), delavirdine (trade name: Rescriptor), efavirenz(trade name: Sustiva, Stocrin), capravirine (AG1549), and the like.

Examples of the protease inhibitors include indinavir (trade name:Kurikisiban), ritonavir (trade name: norvir), nelfinavir (trade name:Viracept), saquinavir (trade name: Invirase, Fortovase), amprenavir(trade name: agenerase), lopinavir (trade name: Kaletra), atazanavir(trade name: Reyataz), fosamprenavir (trade name: lexiva), tipranavirand the like.

Examples of the chemokine antagonists include endogenous ligands of achemokine receptor, or derivatives and nonpeptidic low molecularcompounds thereof, an antibody against a chemokine receptor and thelike.

Examples of the endogenous ligands of the chemokine receptor includeMIP-1α, MIP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP-4, eotaxin,MDC and the like.

Examples of the derivative of the endogenous ligands include AOP-RANTES,Met-SDF-1α, Met-SDF-1β and the like.

Examples of the antibody of the chemokine receptor include Pro-140 andthe like.

Examples of the CCR2 antagonists include compounds described inWO99/07351, WO99/40913, WO00/46195, WO00/46196, WO00/46197, WO00/46198,WO00/46199, WO00/69432, WO00/69815, and Bioorg. Med. Chem. Lett., 10,1803 (2000), and the like.

Examples of the CCR3 antagonists include compounds described inDE19837386, WO99/55324, WO99/55330, WO00/04003, WO00/27800, WO00/27835,WO00/27843, WO00/29377, WO00/31032, WO00/31033, WO00/34278, WO00/35449,WO00/35451, WO00/35452, WO00/35453, WO00/35454, WO00/35876, WO00/35877,WO00/41685, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172,WO00/53600, WO00/58305, WO00/59497, WO00/59498, WO00/59502, WO00/59503,WO00/62814, WO00/73327, and WO01/09088, and the like.

Examples of the CCR4 antagonists include compounds described inWO02/030357 and WO02/030358, and the like.

Examples of the CCR5 antagonists include compounds described inWO99/17773, WO99/32100, WO00/06085, WO00/06146, WO00/10965, WO00/06153,WO00/21916, WO00/37455, EP1013276, WO00/38680, WO00/39125, WO00/40239,WO00/42045, WO00/53175, WO00/42852, WO00/66551, WO00/66558, WO00/66559,WO00/66141, WO00/68203, JP2000-309598, WO00/51607, WO00/51608,WO00/51609, WO00/51610, WO00/56729, WO00/59497, WO00/59498, WO00/59502,WO00/59503, WO00/76933, WO98/25605, WO99/04794, WO99/38514 and Bioorg.Med. Chem. Lett., 10, 1803 (2000), TAK-779, SCH-351125 (SCH-C),SCH-417690 (SCH-D), UK-427857, GW 873140A (ONO-4128), TAK-220, TAK-652,and the like.

Examples of the CXCR4 antagonists include AMD-3100, AMD-070, T-22,KRH-1120, KRH-1636, KRH-2731, CS-3955, and compounds described inWO00/66112, WO2004/024697, WO2004/052862, EP01493438, JP2002-371042,JP2004-196769, US2004/0132642, US2005/0192272, US2005/0215543,US2005/0215544, US2005/0215545, WO99/36091, WO02/094261, WO02/096397,WO03/029218, WO03079020, WO2004/020462, WO2004/024178, WO2004/024697,WO2004/054603, WO2004/059285, WO2004/087068, WO2004/093817,WO2004/096838, WO2004/096839, WO2004/096840, WO2005/002522,WO2005/002551, WO2005/025565, WO2005/085209, WO2005/085219,WO2006/020415, WO2006/022454, WO2006/023400, WO2006/039252, and thelike.

Examples of the fusion inhibitors include T-20 (pentafuside) T-1249, andthe like.

Examples of the HIV integrase inhibitors include Equisetin, Temacrazine,PL-2500, V-165, NSC-618929, L-870810, L-708906 analog, S-1360, 1838 andthe like.

The Short Interfering short-interfering RNAs targeting a HIV-relatedfactor include those which target a gene of a HIV-related factor.Examples of the HIV-related factors include reverse transcriptase,protease, chemokine (CCR2, CCR3, CCR4, CCR5, CXCR4, etc.), CD4, HIV(HIV1, HIV2, etc.) and the like.

The conventional clinical dosage of typical reverse transcriptaseinhibitors and protease inhibitors is, for example, as described below,but is not limited thereto in the present invention.

Zidovudine: 100 mg capsule, three times per day in a dosage of 200 mg;300 mg tablet, twice per day in a dosage of 300 mg;

Didanosine: 25 to 200 mg tablet, twice per day in a dosage of 125 to 200mg;

Zalcitabine: 0.375 mg to 0.75 mg tablet, three times per day in a dosageof 0.75 mg;

Stavudine: 15 to 40 mg capsule, twice per day in a dosage of 30 to 40mg;

Lamivudine: 150 mg tablet, twice per day in a dosage of 150 mg;

Abacavir: 300 mg tablet, twice per day in a dosage of 300 mg;

Nevirapine: 200 mg tablet, once per day for 14 days in a dosage of 200mg, followed by twice per day;

Delavirdine: 100 mg tablet, three times per day in a dosage of 400 mg;

Efavirenz: 50 to 200 mg capsule, once per day in a dosage of 600 mg;

Indinavir: 200 to 400 mg capsule, three times per day in a dosage of 800mg;

Ritonavir: 100 mg capsule, twice per day in a dosage of 600 mg;

Nelfinavir: 250 mg tablet, three times per day in a dosage of 750 mg;

Saquinavir: 200 mg capsule, three times per day in a dosage of 1,200 mg;

Amprenavir: 50 to 150 mg tablet, twice per day in a dosage of 1,200 mg.

Examples of the other drugs for complementation and/or enhancement ofthe preventive and/or therapeutic effects of the compound of the presentinvention against asthma include antihistaminic agents, antiallergicagents (chemical mediator release inhibitors, histamine antagonists,thromboxane synthetase inhibitors, thromboxane antagonists, Th2 cytokineinhibitors), steroids, bronchodilator agents (xanthine derivatives,sympathomimetic agents, parasympathomimetic agents), vaccinotherapeuticagents, gold preparations, Chinese medicines, basic nonsteroidalanti-inflammatory drugs, 5-lipoxygenase inhibitors, 5-lipoxygenaseactivation protein antagonists, leukotriene synthesis inhibitors,prostaglandins, cannabinoid-2 receptor stimulants, antitussive drugs,expectorants, and the like.

Examples of the antihistaminic agents include diphenhydramine,diphenylpyraline hydrochloride, diphenylpyraline chlorotheophyllinate,clemastine fumarate, dimenhydrinate, dl-chlorpheniramine maleate,d-chlorpheniramine maleate, triprolidine hydrochloride, promethazinehydrochloride, alimemazine tartrate, isothipendyl hydrochloride,homochlorcyclizine hydrochloride, hydroxyzine, cyproheptadinehydrochloride, levocabastine hydrochloride, astemizole, bepotastine,desloratadine, TAK-427, ZCR-2060, NIP-530, mometasone furoate,mizolastine, BP-294, andolast, auranofin, acrivastine and the like.

Examples of the chemical mediator release inhibitors include disodiumcromoglycate, tranilast, amlexanox, repirinast, ibudilast, pemirolastpotassium, tazanolast, nedocromil, cromoglicate, israpafant and thelike.

Examples of the histamine antagonists include ketotifen fumarate,azelastine hydrochloride, oxatomide, mequitazine, terfenadine,emedastine fumarate, epinastine hydrochloride, ebastine, cetirizinehydrochloride, olopatadine hydrochloride, loratadine, fexofenadine andthe like.

Examples of the thromboxane synthetase inhibitors include ozagrelhydrochloride imitrodast sodium and the like.

Examples of the thromboxane antagonists include seratrodast, ramatroban,domitroban calcium hydrate, KT-2-962 and the like.

Examples of the Th2 cytokine inhibitors include suplatast tosilate andthe like.

Examples of the steroids include, for example, external medicine such asclobetasol propionate, diflorasone diacetate, fluocinonide, mometasonefuroate, betamethasone dipropionate, betamethasone butyrate propionate,betamethasone valerate, difluprednate, budesonide, diflucortolonevalerate, amcinonide, halcinonide, dexamethasone, dexamethasonepropionate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate acetate,fluocinolone acetonide, beclometasone dipropionate, triamcinoloneacetonide, flumetasone pivalate, alclometasone propionate, clobetasonebutyrate, prednisolone, beclomethasone propionate, fludroxycortide, andthe like.

Examples of the xanthine derivative include aminophylline, theophylline,doxophylline, cipamfylline, diprophylline, proxyphylline, and cholinetheophylline.

Examples of the sympathomimetic agents include epinephrine, ephedrinehydrochloride, dl-methylephedrine hydrochloride, methoxyphenaminehydrochloride, isoproterenol sulfate, isoproterenol hydrochloride,orciprenaline sulfate, chloroprenaline hydrochloride, trimetoquinolhydrochloride, salbutamol sulfate, terbutaline sulfate, hexoprenalinesulfate, tulobuterol hydrochloride, procaterol hydrochloride, fenoterolhydrobromate, formoterol fumarate, clenbuterol hydrochloride, mabuterolhydrochloride, salmeterol xinafoate, R,R-formoterol, tulobuterol,pirbuterol hydrochloride, ritodrine hydrochloride, bambuterol,dopexamine hydrochloride, meluadrine tartrate, AR-C68397,levosalbutamol, KUR-1246, KUL-7211, AR-C89855, S-1319 and the like.

Examples of the parasympathomimetic agents include ipratropium bromide,flutropium bromide, oxitropium bromide, cimetropium bromide, temiverine,tiotropium bromide, revatropate (UK-112166) and the like.

Examples of the vaccinotherapeutic agents include paspat, asthremedin,Broncasma Berna, CS-560 and the like.

Examples of the gold preparations include gold sodium thiomalate and thelike.

Examples of the basic nonsteroidal anti-inflammatory drugs includetiaramide hydrochloride, tinoridine hydrochloride, epirizole, emorfazoneand the like.

Examples of the 5-lipoxygenase inhibitors include zyleuton, docebenone,piriprost, SCH-40120, WY-50295, E-6700, ML-3000, TMK-688, ZD-2138,dalbufelone mesilate, R-68151, E-6080, DuP-654, SC-45662, CV-6504,NE-11740, CMI-977, NC-2000, E-3040, PD-136095, CMI-392, TZI-41078,Orf-20485, IDB-18024, BF-389, A-78773, TA-270, FLM-5011, CGS-23885,A-79175, ETH-615 and the like.

Examples of the 5-lipoxygenase activation protein antagonists includeMK-591, MK-886 and the like.

Examples of the leukotriene synthesis inhibitors include auranofin,proglumetacin maleate, L-674636, A-81834, UPA-780, A-93178, MK-886,REV-5901A, SCH-40120, MK-591, Bay-x-1005, Bay-y-1015, DTI-0026,Amlexanox, E-6700 and the like.

Examples of the prostaglandins (hereinafter abbreviated to as PG)include PG receptor agonists, PG receptor antagonists and the like.

Examples of the PG receptor include PGE receptor (EP1, EP2, EP3, andEP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP), TXreceptor (TP) and the like.

Examples of the antitussive drugs include codeine phosphate,dihydrocodeine phosphate, oxymetebanol, dextromethorphan hydrobromate,pentoxyverine citrate, dimemorfan phosphate, oxeladin citrate,cloperastine, benproperine phosphate, clofedanol hydrochloride,fominoben hydrochloride, noscapine, tipepidine hibenzate, eprazinonehydrochloride, plantago herb extract and the like.

Examples of the expectorants include foeniculated ammonia spirit, sodiumhydrogencarbonate, potassium iodide, bromhexine hydrochloride, cherrybark extract, carbocysteine, fudosteine, ambroxol hydrochloride,ambroxol hydrochloride sustained-release tablet, methylcysteinehydrochloride, acetylcysteine, L-ethylcysteine hydrochloride, tyloxapoland the like.

Examples of the other drugs for complementation and/or enhancement ofthe preventive and/or therapeutic effects against atopic dermatitis(urticaria, etc.) of the compound of the present invention includesteroids, non-steroid anti-inflammatory drug (NSAID), immune inhibitor,prostaglandins, antiallergic agent, mediator release inhibitor,antihistaminic agent, forskolin preparation, phosphodiesteraseinhibitor, cannabinoid-2 receptor stimulant and the like.

Examples of the other drugs for complementation and/or enhancement ofthe preventive and/or therapeutic effects against allergic diseases(allergic bronchopulmonary aspergillosis, allergic eoisinophilicgastroenteritis, etc.) of the compound of the present invention includeantiasthmatic drug, inhaled steroid drug, inhaled β2 stimulant,methylxanthine-based stimulant, antiallergic agent, anti-inflammatoryagent, anticholinergic agent, thromboxane antagonist, leukotrieneantagonist, LTD4 antagonist, PAF antagonist, phosphodiesteraseinhibitor, β2 agonist, steroid drug, mediator release inhibitor,eosinophile leu kocytechemotaxis inhibitor, macrolide-based antibiotic,immune inhibitor, hyposensitization (allergen) injection and the like.

Examples of the antiasthmatic drug include theophylline, procaterol,ketotifen, azelastine and the like.

Examples of the inhaled steroid drug include beclomethasone,fluticasone, budesonide and the like.

Examples of the inhaled β2 stimulant include fenoterol, salbutamol,formoterol, salmeterol and the like.

Examples of the methylxanthine-based stimulant include theophylline andthe like.

Examples of the antiallergic agent include ketotifen, terfenadine,azelastine, epinastine, suplatast, disodium cromoglycate and the like.

Examples of the anti-inflammatory agent include dichlofenac sodium,ibuprofen, indomethacin and the like.

Examples of the anticholinergic agent include ipratropium bromide,flutropium bromide, oxitropium bromide, tiotropium bromide and the like.

Examples of the thromboxane antagonist include ozagrel, seratrodast andthe like.

Examples of the macrolide-based antibiotic include erythromycin,roxithromycin and the like.

Examples of the leukotriene antagonist include pranlukast, montelukast,zafirlukast, zyleuton and the like.

Examples of the immune inhibitor include cyclosporine, tacrolimus,FTY720, and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against hepatitis of the compoundof the present invention include liver hydrolysate preparation,polyenephosphatidylcholine, glycyrrhizin preparation, protoporphyrinsodium, ursodeoxycholic acid, steroids, anticholinergic agent, gastricantiacid, propagermanium, lipid peroxidase inhibitor, and mitochondrialbenzodiazepine receptor antagonist.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against arthritis and rheumatoidarthritis of the compound of the present invention includemetalloproteinase inhibitor, immune inhibitor, non-steroidanti-inflammatory drug (NSAID), steroid drug, prostaglandins,phosphodiesterase inhibitor, cannabinoid-2 receptor stimulant, diseasemodifying anti-rheumatic drug (slow-acting anti-rheumatic drug),anti-inflammatory enzyme preparation, cartilage protective agent, T cellinhibitor, TNFα inhibitor, prostaglandin synthetase inhibitor, IL-6inhibitor, interferon γ agonist, IL-1 inhibitor and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against psoriasis of the compoundof the present invention include steroids, vitamin D derivative and thelike.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against rhinitis of the compoundof the present invention include antihistaminic agent, mediator releaseinhibitor, thromboxane synthetase inhibitor, thromboxane A₂ receptorantagonist, leukotriene receptor antagonist, steroids, a adrenalinreceptor stimulant, xanthine derivative, anticholinergic agent,prostaglandins, nitrogen monoxide synthetase inhibitor, β₂ adrenalinreceptor stimulant, phosphodiesterase inhibitor, cannabinoid-2 receptorstimulant and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against conjunctivitis of thecompound of the present invention include leukotriene receptorantagonist, antihistaminic agent, mediator release inhibitor,non-steroid anti-inflammatory drug, prostaglandins, steroid drug,nitrogen monoxide synthetase inhibitor, cannabinoid-2 receptor stimulantand the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against multiple sclerosis of thecompound of the present invention include immune inhibitor,cannabinoid-2 receptor stimulant and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against ulcerative colitis of thecompound of the present invention include mesalazine,salazosulfapyridine, digestive tract ulcer therapeutic substance,anticholinergic agent, steroid drug, 5-lipoxygenase inhibitor,antioxidant, LTB4 antagonist, local anesthetic, immune inhibitor,protection factor enhancer, MMP inhibitor, and mitochondrialbenzodiazepine receptor antagonist.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against diabetic complication ofthe compound of the present invention include sulfonyl urea-basedhypoglycemic agent, biguanide-based drug, α-glucosidase inhibitor,ultrashort-acting insulinotropic agent, insulin drug, PPAR agonist,insulin sensitive enhancer having no PPAR antagonism, β3 adrenalinreceptor agonist, aldose reductase inhibitor, dipeptidyl peptidase IVinhibitor and the like.

Examples of the sulfonyl urea-based hypoglycemic agent includeacetohexamide, glibenclamide, gliclazide, glyclopyramide,chlorpropamide, tolazamide, tolbutamide, Glimepiride and the like.

Examples of the biguanide-based drug include buformin hydrochloride,metformin hydrochloride and the like.

Examples of the α-glucosidase inhibitor include acarbose, voglibose andthe like.

Examples of the ultrashort-acting insulinotropic agent includenateglinide, repaglinide and the like.

Examples of the PPAR agonist include pioglitazone, troglitazone,rosiglitazone, JTT-501, and the like.

Examples of the insulin sensitive enhancer having no PPAR antagonisminclude ONO-5816, YM-440 and the like.

Examples of the β3 adrenalin receptor agonist include AJ9677, L750355,CP331648 and the like.

Examples of the aldose reductase inhibitor include epalrestat,fidarestat, zenarestat and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against cancer (malignant tumor)and cancer metastasis of the compound of the present invention includeanticancer agent (for example, MMP inhibitor, alkylation agent (forexample, cyclophosphamide, melphalan, thiotepa, mytomycin C, busulfan,procarbazine hydrochloride, etc.), antimetabolite (for example,methotrexate, mercaptpurine, azathiopurine, fluorouracil, tegafur,cytarabine, azaserine, etc.), antibiotic (for example, mytomycin C,bleomycin, Peplomycin, doxorubicin hydrochloride, aclarubicin,daunorubicin, actinomycin D, etc.), mitosis inhibitor, platinum complex(for example, Cisplatin), plant-derived antineoplastic agent (forexample, vincristine sulfate, vinblastine sulfate, etc.), anticanceroushormone (for example, methyltestosterone, testosterone propionate,testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate,etc.), immunopotentiator (for example, picibanil, krestin, etc.), andinterferon (for example, IFNα, IFNα-2a, IFNα-2b, IFNβ, IFNγ-1a, etc.).Examples thereof include biologics capable of conducting T cellactivation (for example, anti-CTLA-4 antibody, anti-PD-1 antibody,etc.), antiangiogenic agent (for example, bevacizumab, pegaptanib,SU-6668, vatalanib, ranibizumab, sorafenib, SU-11248, neovastat), etc.),and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against immune disease (forexample, autoimmune disease, transplanted organ rejection, etc.) of thecompound of the present invention include immune inhibitor (for example,cyclosporine, tacrolimus, FTY720, etc.) and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against dementia such as Seniledementia with Alzheimer's type of the compound of the present inventioninclude acetylcholine esterase inhibitor, nicotinic receptor modifier,cerebral ameliorator, monoamineoxidase inhibitor, vitamin E, aldosereductase inhibitor and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against epilepsia of the compoundof the present invention include phenyloin, trimethadione, ethosuximide,carbamazepine, phenobarbitone, primidone, acetazolamide, sultiame,sodium valproate, clonazepam, diazepam, nitrazepam and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against arteriosclerosis of thecompound of the present invention include HMG-CoA reductase inhibitor,fibrates, probucol preparation, anion-exchange resin, EPA preparation,nicotinic acid preparation, MTP inhibitor, other anti-high cholesterolagent, EDG-2 antagonist and the like.

Examples of the other drug for complementation and/or enhancement of theeffects when the compound of the present invention is used in aregeneration therapy include cytokines and various growth factors, forexample, various CSFs (for example, G-CSF, GM-CSF, etc.), variousinterleukins (for example, IL-3,6,7, 11, 12, etc.), EPO, TPO, SCF, FLT3ligand, MIP-1α and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against retinopathy of thecompound of the present invention include antiangiogenic agent (forexample, bevacizumab, pegaptanib, SU-6668, vatalanib, ranibizumab,sorafenib, SU-11248, neovastat, etc.) and the like.

Examples of other drugs for complementation and/or enhancement of thepreventive and/or therapeutic effect against infections of the compoundof the present invention include antibiotics, synthetic antimicrobials,anti-viral drugs, and the like.

Examples of the antibiotic include cefuroxime sodium, meropenemtrihydrate, netilmicin sulfate, sisomicin sulfate, ceftibuten, PA-1806,IB-367, tobramycin, PA-1420, doxorubicin, astromicin sulfate, cefetametpivoxil hydrochloride, and the like. Examples of the antibiotic used ininhalation include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin,astromicin sulfate, cefetamet pivoxil hydrochloride, and the like.

Examples of the anti-viral drug include amantadine, rimantadine,oseltamivir, zanamivir, and the like.

Examples of the synthetic antimicrobial include quinolone-basedantibiotic, sulfa drug, ST mixture, and the like.

Of the synthetic antimicrobials, the quinolone-based antibioticincluded, for example, norfloxacin, enoxacin, ciprofloxacinhydrochloride, ofloxacin, lomefloxacin hydrochloride, tosufloxacintosylate, sparfloxacin, fleroxacin, levofloxacin, and the like.

Of synthetic antimicrobials, the sulfa drug includes, for example,dimexine, sulxin, sulfadimethoxine, and the like.

The compound of the present invention is safe and has low toxicity andtherefore can be administered to human and mammal other than human (forexample, rat, mouse, rabbit, sheep, pig, cow, cat, dog, monkey, etc.).

In order to use a pharmaceutical composition comprising the compound ofthe present invention or a concomitant drug of the compound of thepresent invention and other drugs, it is commonly administered,systematically or locally, in an oral or parenteral dosage form.

The dosage of the pharmaceutical preparation varies depending on theage, body weight, symptom, the desired therapeutic effect, the route ofadministration and duration of treatment. For the human adult, thedosage per person is between 1 ng and 1000 mg, by oral administration,up to several times per day, between 0.1 ng and 100 mg, by parenteraladministration, or continuous administration 1 hour to 24 hours per dayfrom vein.

As a matter of course, since the dosage varies under various conditionsas is described above, the dosage may be sometimes sufficient which issmaller than the above range, or sometimes the dosage must be more thanthe above range.

In case of administering a pharmaceutical composition comprising thecompound of the present invention, or a concomitant drug of the compoundof the present invention and other drugs, it is used as solidpreparations for internal use and solutions for internal use for oraladministration, and injections, external preparations, suppositories,ophthalmic solutions, nasal drops, inhalants and the like for parenteraladministration.

Examples of the solid preparation for internal use for oraladministration include tablets, pills, capsules, powders, and granules.Capsules include hard capsules and soft capsules.

In such a solid preparation for internal use, one or more activesubstances are used as they are, or used after mixing with excipients(lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.),binders (hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesiumaluminometasilicate, etc.), disintegrants (calcium carboxymethylcellulose, etc.), lubricants (magnesium stearate, etc.), stabilizers andsolubilizing agents (glutamic acid, aspartic acid, etc.) and forminginto a preparation according to a conventional method. If necessary, thepreparation may be coated with a coating agent (saccharose, gelatin,hydroxypropyl cellulose, hydroxylpropylmethy cellulosephthalate, etc.)or may be coated with two or more layers. Furthermore, capsules made ofan absorbable substance such as gelatin is included.

The solutions for internal use for oral administration includepharmaceutically acceptable water, suspensions, emulsions, syrups, andelixirs. In such a solution, one or more active substances aredissolved, suspended or emulsified in a diluent used commonly (purifiedwater, ethanol, mixed solution thereof, etc.). Furthermore, thissolution may contain humectants, suspending agents, emulsifiers,sweeteners, flavors, aromatics, preservatives, buffers, and the like.

The dosage form of the external preparation for parenteraladministration includes, for example, ointment, gel, cream, fomentation,patch, liniment, propellant, inhalant, spray, aerosol, ophthalmicsolution, and nasal drop. These products contain one or more activesubstances and are prepared according to the formulation which is knownor commonly used.

An ointment is prepared in accordance with a well known formulation or acommonly employed formulation. For example, it is prepared bytriturating or dissolving one or more active substances in a base. Anointment base is selected from well known ones or those commonlyemployed. For example, those selected from higher fatty acids or higherfatty acid esters (adipic acid, myristic acid, palmitic acid, stearicacid, oleic acid, adipate ester, myristate ester, palmitate ester,stearate ester, oleate ester, etc.), waxes (beeswax, whale wax, ceresin,etc.), surfactants (polyoxyethylene alkyl ether phosphate ester, etc.),higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.),silicone oils (dimethylpolysiloxane, etc.), hydrocarbons (hydrophilicpetrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.),glycols (ethylene glycol, diethylene glycol, propylene glycol,polyethylene glycol, macrogol, etc.), vegetable oils (castor oil, oliveoil, sesame oil, turpentine oil, etc.), animal oils (mink oil, egg yolkoil, squalane, squalene, etc.), water, absorption accelerators, agentsfor preventing contact dermatitis are used alone or in combination.Furthermore, it may contain humectants, preservatives, stabilizers,antioxidizing agents, flavors, and the like.

A gel is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving one or moreactive substances in a base. A gel base is selected from a base which isknown or commonly used. For example, those selected from lower alcohols(ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethylcellulose, etc.), neutralizers (triethanolamine, diisopropanolamine,etc.), surfactants (monostearic acid polyethylene glycol, etc.), gums,water, absorption accelerator, and agent for preventing contactdermatitis are used alone or in combination. Furthermore, it may containpreservatives, antioxidizing agents, and flavoring agent.

A cream is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving or emulsifyingone or more active substances in a base. A cream base is selected from abase which is known or commonly used. For example, those selected fromhigher fatty acid esters, lower alcohols, hydrocarbons, polyhydricalcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols(2-hexyl decanol, cetanol, etc.), emulsifiers (polyoxyethylene alkylethers, fatty acid esters, etc.), water, absorption accelerators, andagents for preventing contact dermatitis are used alone or incombination. Furthermore, it may contain preservatives, antioxidizingagents, and flavoring agents.

A fomentation is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving one or moreactive substances in a base to obtain a kneaded mixture and spreadingthe kneaded mixture over a substrate. A fomentation base is selectedfrom a base which is known or commonly used. For example, those selectedfrom thickeners (polyacrylic acid, polyvinyl pyrrolidone, gum arabic,starch, gelatin, methyl cellulose, etc.), humectants (urea, glycerin,propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium,magnesium, etc.), water, solubilizing agents, tackifiers, and agents forpreventing contact dermatitis are used alone or in combination.Furthermore, it may contain preservatives, antioxidizing agents, andflavoring agent.

A patch is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving one or moreactive substances in a base, and spreading the solution over asubstrate. A patch base is selected from a base which is known orcommonly used. For example, those selected from polymer bases, fats andoils, higher fatty acids, tackifiers, and agents for preventing contactdermatitis are used alone or in combination. Furthermore, it may containpreservatives, antioxidizing agents, and flavoring agent.

A liniment is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving, suspending oremulsifying one or more active substances in one or more kinds selectedfrom water, alcohol (ethanol, polyethylene glycol, etc.), higher fattyacid, glycerin, soap, emulsifier, and suspending agent. Furthermore, itmay contain preservatives, antioxidizing agents, and flavoring agent.

A propellant, an inhalant, and a spray may contain, in addition to adiluent used commonly, a stabilizer such as sodium hydrogensulfite and abuffer capable of imparting isotonicity, for example, an isotonicitysuch as sodium chloride, sodium citrate or citric acid.

An injection for parenteral administration includes all injections andalso includes a drop. For example, it includes intramuscular injection,subcutaneous injection, endodermic injection, intraarterial injection,intravenous injection, intraperitoneal injection, intraspinal injection,and intravenous drop.

The injection for parenteral administration includes solutions,suspensions, emulsions, and solid injections used by dissolving orsuspending in a solvent before use. The injection is used afterdissolving, suspending, or emulsifying one or more active substances ina solvent. As the solvent, for example, distilled water for injection,physiological saline, vegetable oil, and alcohols such as propyleneglycol, polyethylene glycol or ethanol are used alone or in combination.Furthermore, the injection may contain stabilizers, solubilizing agents(glutamic acid, aspartic acid, polysolvate 80®, etc.), suspendingagents, emulsifiers, soothing agents, buffers, and preservatives. Theseinjections are prepared by sterilizing in the final process, or preparedby an aseptic treatment. Also, a sterile solid, for example, afreeze-dried product is prepared and can be used after dissolving insterilized distilled water or distilled water for sterile injection, orthe other solvent before use.

An ophthalmic solution for parenteral administration includes ophthalmicsolution, suspension type ophthalmic solution, emulsion type ophthalmicsolution, ophthalmic solution soluble when used, and eye ointment.

These ophthalmic solutions are prepared according to a known method. Forexample, one or more active substances are dissolved, suspended oremulsified in a solvent before use. As the solvent for ophthalmicsolution, for example, sterilized purified water, physiological saline,and other aqueous solvent or non-aqueous agent for injection (forexample, vegetable oil, etc.) are used alone or in combination. Ifnecessary, the ophthalmic solution may contain appropriately selectedisotonizing agents (sodium chloride, concentrated glycerin, etc.),buffering agents (sodium phosphoate, sodium acetate, etc.), surfactants(polysolvate 80 (trade name), polyoxyl 40 stearate, polyoxyethylenehardened castor oil, etc.), stabilizers (sodium citrate, sodium edetate,etc.), and antiseptics (benzalkonium chloride, paraben, etc.) Theseophthalmic solutions are prepared by sterilizing in the final process,or prepared by an aseptic treatment. Also, a sterile solid, for example,a freeze-dried product is prepared and can be used after dissolving insterilized distilled water or distilled water for sterile injection, orthe other solvent before use.

An inhalant for parenteral administration includes aerozol, inhalationpowder, and inhalation solution, and the inhalation solution may be sucha configuration that it is used after dissolving in water or othersuitable medium at the point of use.

These inhalants are prepared according to a known method.

For example, an inhalation solution is prepared by appropriatelyselecting antiseptics (benzalkonium chloride, paraben, etc.), colorants,buffering agents (sodium phosphate, sodium acetate, etc.), isotonizingagents (sodium chloride, concentrated glycerin, etc.), thickeners(carboxyvinyl polymer, etc.), and absorption accelerator, if necessary.

An inhalation powder is prepared by appropriately selecting lubricants(stearic acid and a salt thereof, etc.), binders (starch, dextrin,etc.), excipients (lactose, cellulose, etc.), colorants, antiseptics(benzalkonium chloride, paraben, etc.), and absorption accelerator ifnecessary.

In case of administering the inhalation solution, a spraying apparatus(atomizer, nebulizer) is commonly used. In case of administering theinhalation powder, an inhalation administration apparatus for powder iscommonly used.

The other composition for parenteral administration includessuppositories for intrarectal injection and pessaries for vaginaladministration, which contain one or more active substances and areformulate by a conventional method.

Designation of the compound of the present invention is described below.

The compounds used in the present invention were commonly designatedusing a computer program ACD/Name Batch® (manufactured by AdvancedChemistry Development Inc.) which designates according to the regulationof IUPAC, or commonly designated according to IUPAC Nomenclature. Forexample, a compound wherein A¹ and A² represent an imidazol-2-yl group,B¹ and B² represent a methylene group, G represents a carbon atomsubstituted by a oxo group, E represents a 1,4-phenylene group, Lrepresents —CH₂—NH—, and J represents atrans-4-(1-piperidinyl)cyclohexyl group, namely, a compound representedby the following formula:

is designated asN,N-bis(1H-imidazol-2-ylmethyl)-4-({[trans-4-(1-piperidinyl)cyclohexyl]amino}methyl)benzamide.

EXAMPLES

The present invention is described in detail based on Examples, but thepresent invention is not limited thereto.

Crystallinity of the compound, to which properties had been described,was confirmed using a polarizing microscope.

The point of separation by chromatography and the solvent in theparentheses shown in TLC indicate a dissolution medium or an eluentused, and the proportion indicates a volume ratio.

NMR is a measured value of ¹HNMR at 300 MHz and the solvent shown in theparentheses of NMR indicates a solvent used in the measurement.

Example 1 2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide

To an acetonitrile (500 mL) solution of 1H-imidazole-2-carboaldehyde (64g) and triethylamine (140 mL), dimethylsulfamoyl chloride (100 g) wasadded at room temperature. The reaction solution was stirred at 50° C.for 16 hours. After the reaction solution was cooled to roomtemperature, the precipitated crystal was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue was washedwith ethyl acetate to obtain the crude title compound. The washing waswashed with saturated brine and then dried over anhydrous sodiumsulfate. After removing the anhydrous sodium sulfate by filtration, thefiltrate was concentrated. The residue was purified by silica gelchromatography (ethyl acetate) to obtain the crude title compound. Theobtained compound was combined with the crystal obtained previously andthen washed with ether to obtain the title compound (88.32 g) having thefollowing physical properties.

TLC: Rf 0.64 (ethyl acetate);

NMR (CDCl₃): δ 9.94 (s, 1H), 7.59 (m, 1H), 7.30 (m, 1H), 3.01 (s, 6H).

Example 22,2′-[(benzylimino)bis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

To a 1% acetate-N,N-dimethylformamide (500 mL) solution of the compound(70 g) obtained in Example 1, benzylamine (17.9 mL) was added at 0° C.To the solution, sodium triacetoxyboron (52 g) was added. The reactionsolution was stirred at 0° C. for 30 minutes. To the reaction solution,sodium triacetoxyboron (52 g) was added. The reaction solution washeated to room temperature and then stirred at room temperature for 40hours. The reaction solution was concentrated under reduced pressure. Tothe residue, an aqueous 5N sodium hydroxide solution was added, therebyadjusting the pH to 12. The aqueous layer was extracted with ethylacetate. The combined organic layer was washed with saturated brine andthen dried over anhydrous magnesium sulfate. After removing theanhydrous sodium sulfate by filtration, the filtrate was concentrated.Without purifying the residue, the title compound (79 g) having thefollowing physical properties was obtained.

TLC: Rf 0.38 (ethyl acetate:methanol:28% aqueous ammonia=90:10:2);

NMR (CDCl₃): δ 7.25 (m, 7H), 6.98 (m, 2H), 4.19 (s, 4H), 4.09 (s, 2H),2.79 (s, 12H).

Example 32,2′-[iminobis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

To an ethanol (350 mL) solution of the compound (55.7 g) obtained inExample 2, 20% palladium hydroxide-carbon (13.6 g) was added under anargon atmosphere. The reaction mixture was stirred under a hydrogenatmosphere at 60° C. for 6 hours. The reaction mixture was cooled toroom temperature and then filtered through Celite. The filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (ethyl acetate:10%-saturated aqueousammonia-methanol=1:0→8:2) to obtain the title compound (28.5 g) havingthe following physical properties.

TLC: Rf 0.66 (dichrolomethane:methanol:28% aqueous ammonia=80:20:3);

NMR (CDCl₃): δ 7.22 (m, 2H), 6.96 (m, 2H), 4.14 (s, 4H), 2.90 (s, 12H).

Example 4N,N-bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)-4-formylbenzamide

To an N,N-dimethylformamide (100 mL) solution of 4-formylbenzoic acid(9.57 g), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride(12.21 g) was added at 0° C. The reaction solution was stirred at 0° C.for one hour. To the solution, the compound (20.78 g) obtained inExample 3 was added. The reaction solution was heated to roomtemperature and then stirred for 4 hours. The reaction solution wasconcentrated under reduced pressure. To the residue, an aqueoussaturated sodium hydrogen carbonate solution was added. The aqueouslayer was extracted with ethyl acetate. The aqueous layer was combinedwith the organic layer, washed in turn with 1N hydrochloric acid, waterand saturated brine, and then dried over anhydrous sodium sulfate. Afterremoving the anhydrous sodium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(ethyl acetate: 10%-saturated aqueous ammonia-methanol=1:0→8:2) toobtain the title compound (21.27 g) having the following physicalproperties.

TLC: Rf 0.52 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 10.01 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz,2H), 7.26 (m, 1H), 7.22 (m, 1H), 7.09 (m, 1H), 7.00 (m, 1H), 5.06 (s,2H), 4.94 (s, 2H), 3.03 (s, 6H), 2.65 (s, 6H).

Example 5 4-formyl-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

To the compound (27.28 g) obtained in Example 4, 2N hydrochloric acid(135 mL) was added. The mixture was stirred at 80° C. for 2 hours. Afterthe reaction solution was cooled to room temperature, an aqueous 5Nsodium hydroxide solution was added until the pH is adjusted to 12. Tothe aqueous layer, sodium chloride was added, followed by extractionwith ethyl acetate. The combined organic layer was washed with saturatedbrine and then dried over anhydrous sodium sulfate. After removing theanhydrous sodium sulfate by filtration, the filtrate was concentrated.The residue was purified by silica gel chromatography (ethyl acetate:10%-saturated aqueous ammonia-methanol=1:0→8:2) to obtain the titlecompound (10.49 g) having the following physical properties.

TLC: Rf 0.61 (methanol:28% aqueous ammonia=99:1);

NMR (CDCl₃): δ 10.03 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz,2H), 7.26 (m, 1H), 7.22 (m, 1H), 7.09 (m, 1H), 7.00 (m, 1H), 4.68 (s,2H), 4.56 (s, 2H).

Example 6 Tert-butyl (trans-4-piperidin-1-ylcyclohexyl)carbamate

Trans-4-tert-butoxycarbonylamino-aminocyclohexane (1 g) and potassiumcarbonate (1.3 g) were suspended in ethanol (20 mL), and then1,5-dibromopentane (1.07 g) was added thereto. The reaction solution wasstirred at 80° C. for 48 hours. After the reaction solution was cooledto room temperature, the solvent was concentrated under reducedpressure. The residue was dissolved in water (50 mL). The aqueous layerwas extracted twice with dichloromethane (50 mL). The combined organiclayer was washed with saturated brine and then dried over anhydrousmagnesium sulfate. After removing the anhydrous sodium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (ethyl acetate: 10%-saturated aqueousammonia-methanol=1:0→10:1) to obtain the title compound (492 mg) havingthe following physical properties.

TLC: Rf 0.47 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 4.34 (m, 1H), 3.35 (m, 1H), 2.48 (m, 4H), 2.27 (m, 1H),2.04 (m, 2H), 1.88 (m, 2H), 1.57 (m, 4H), 1.44 (s, 9H), 1.68 (m, 1H),1.38 (m, 2H), 1.15 (m, 2H).

Example 7 Trans-4-piperidin-1-ylcyclohexaneamine

To a methanol (4 mL) solution of the compound (480 mg) obtained inExample 6, 4N hydrogen chloride-ethyl acetate solution (4 mL) was addedat 0° C. The reaction solution was stirred at 0° C. for one hour. Thereaction solution was concentrated under reduced pressure, and then anaqueous 2N sodium hydroxide solution (20 mL) was added to the residueuntil the pH is adjusted to 12. The aqueous layer was extracted twicewith dichloromethane (50 mL). The combined organic layer was washed withsaturated brine and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous sodium sulfate by filtration, the filtrate wasconcentrated. The residue was used in the subsequent reaction withoutbeing purified.

TLC: Rf 0.23 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 2.61 (m, 1H), 2.54 (m, 4H), 2.29 (m, 1H), 1.90 (m, 4H),1.62 (m, 6H), 1.46 (m, 2H), 1.31 (m, 2H), 1.13 (m, 2H).

Example 8N,N-bis(1H-imidazol-2-ylmethyl)-4-({[trans-4-(1-piperidinyl)cyclohexyl]amino}methyl)benzamide

The same operation as in Example 2 was performed, except for using thecompound (250 mg) obtained in Example 7 and the compound (212 mg)obtained in Example 5, and then the obtained crude product was purifiedby silica gel chromatography (dichrolomethane:methanol: 28% aqueousammonia=10:1:0→80:10:1) to obtain the title compound (161 mg) having thefollowing physical properties.

Description: amorphous;

TLC: Rf 0.36 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.86-1.07 (m, 2H), 1.08-1.26 (m, 2H), 1.26-1.37 (m,2H), 1.37-1.53 (m, 4H), 1.59-1.76 (m, 2H), 1.82-2.01 (m, 2H), 2.07-2.32(m, 2H), 2.33-2.46 (m, 4H), 3.69 (s, 2H), 4.45-4.69 (m, 4H), 6.75-7.20(m, 4H), 7.31 (d, J=8.10 Hz, 2H), 7.41 (d, J=8.10 Hz, 2H), 11.76-12.84(m, 2H).

Example 8(1) to Example 8(128)

The same operation as in Example 8 was performed, except for usingcorresponding amine in place of trans-4-piperidin-1-ylcyclohexaneamineand corresponding aldehyde in place of4-formyl-N,N-bis(1H-imidazol-2-ylmethyl)benzamide in Example 8, toobtain the following compound.

Example 8(1)4-({[4-(dipropylamino)-2-butyn-1-yl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.44 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.89 (t, J=7.20 Hz, 6H), 1.36-1.64 (m, 4H), 2.31-2.56 (m,4H), 3.33-3.51 (m, 4H), 3.88 (s, 2H), 4.53-4.78 (m, 4H), 6.88-7.12 (m,4H), 7.35 (d, J=8.10 Hz, 2H), 7.52 (d, J=8.10 Hz, 2H).

Example 8(2)4-({[(2-cycloheptyl-1,2,3,4-tetrahydro-7-isoquinolinyl)methyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.38 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 1.32-1.65 (m, 8H), 1.65-1.81 (m, 2H), 1.84-2.01 (m, 2H),2.68-2.93 (m, 5H), 3.71 (s, 2H), 3.74 (s, 2H), 3.77 (s, 2H), 4.47-4.75(m, 4H), 6.89-7.13 (m, 7H), 7.36 (d, J=8.40 Hz, 2H), 7.60 (d, J=8.40 Hz,2H).

Example 8(3)4-({[4-(1,3-dihydro-2H-isoindol-2-yl)cyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide(low polar compound)

Description: amorphous;

TLC: Rf 0.60 (ethyl acetate:methanol:28% aqueous ammonia=80:20:2);

NMR (CDCl₃): δ 1.55-1.94 (m, 8H), 2.55 (m, 1H), 2.73 (m, 1H), 3.82 (s,2H), 3.95 (s, 4H), 4.50-4.72 (m, 4H), 6.90-7.12 (m, 4H), 7.16-7.24 (m,4H), 7.37 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H).

Example 8(4)4-({[4-(1,3-dihydro-2H-isoindol-2-yl)cyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide(high polar compound)

Description: amorphous;

TLC: Rf 0.35 (ethyl acetate:methanol:28% aqueous ammonia=80:20:2);

NMR (CDCl₃): δ 1.18-1.43 (m, 4H), 1.98-2.16 (m, 4H), 2.41 (m, 1H), 2.55(m, 1H), 3.85 (s, 2H), 3.98 (s, 4H), 4.52-4.75 (m, 4H), 6.95-7.10 (m,4H), 7.18-7.22 (m, 4H), 7.38 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H).

Example 8(5)4-{[({trans-4-[(dipropylamino)methyl]cyclohexyl}methyl)(methyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.39 (28% aqueous ammonia:methanol=2:98);

NMR (CDCl₃): δ 0.77-0.89 (m, 10H), 1.32-1.48 (m, 6H), 1.77-1.91 (m, 4H),2.08-2.19 (m, 7H), 2.24-2.36 (m, 4H), 3.44 (s, 2H), 4.60-4.72 (m, 4H),6.95-7.10 (m, 4H), 7.32-7.40 (m, 2H), 7.54-7.62 (m, 2H).

Example 8(6)4-[({4-[cycloheptyl(propyl)amino]cyclohexyl}amino)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide(low polar compound)

Description: amorphous;

TLC: Rf 0.47 (ethyl acetate:methanol:28% aqueous ammonia=90:10:2);

NMR (CDCl₃): δ 0.83 (t, J=7.5 Hz, 3H), 1.30-1.90 (m, 22H), 2.44 (m, 2H),2.56 (m, 1H), 2.76 (m, 1H), 2.86 (m, 1H), 3.77 (s, 2H), 4.55-4.78 (m,4H), 6.98-7.08 (m, 4H), 7.40 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H).

Example 8(7)4-[({4-[cycloheptyl(propyl)amino]cyclohexyl}amino)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide(high polar compound)

Description: amorphous;

TLC: Rf 0.40 (ethyl acetate:methanol:28% aqueous ammonia=90:10:2);

NMR (CDCl₃): δ 0.83 (t, J=7.5 Hz, 3H), 1.05-1.82 (m, 20H), 1.92-2.02 (m,2H), 2.32-2.46 (m, 3H), 2.52 (m, 1H), 2.76 (m, 1H), 3.81 (s, 2H),4.55-4.75 (m, 4H), 6.98-7.10 (m, 4H), 7.36 (d, J=8.1 Hz, 2H), 7.62 (d,J=8.1 Hz, 2H).

Example 8(8)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)-2,6-dimethylbenzamide

Description: amorphous;

TLC: Rf 0.51 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.10-1.30 (m, 6H), 1.58-1.65 (m, 8H), 1.80-1.93 (m, 4H),2.01 (s, 6H), 2.30 (m, 1H), 2.50-2.60 (m, 6H), 3.50 (s, 2H), 4.49 (s,2H), 4.89 (s, 2H), 6.96 (s, 2H), 6.98 (s, 2H), 7.04 (s, 2H).

Example 8(9)3-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.53 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.15-1.30 (m, 6H), 1.58-1.90 (m, 12H), 2.26 (m, 1H),2.44-2.58 (m, 4H), 2.58 (t, J=6.90 Hz, 2H), 3.59 (s, 2H), 4.53 (br-s,2H), 4.70 (br-s, 2H), 7.03 (br-s, 2H), 7.07 (br-s, 2H), 7.38-7.40 (m,2H), 7.57-7.61 (m, 2H).

Example 8(10)4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.50 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.83 (s, 9H), 1.43-1.68 (m, 6H), 1.99 (s, 2H), 2.27-2.48(m, 6H), 2.55 (t, J=6.90 Hz, 2H), 3.58 (s, 2H), 4.50-4.75 (m, 4H),6.86-7.13 (m, 4H), 7.36 (d, J=8.10 Hz, 2H), 7.59 (d, J=8.10 Hz, 2H).

Example 8(11)4-{[[trans-4-(dipropylamino)-4-methylcyclohexyl](methyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.17 (28% aqueous ammonia:methanol=2:98);

NMR (CDCl₃): δ 0.72-0.86 (m, 6H), 0.98 (s, 3H), 1.33-1.49 (m, 8H),1.65-1.79 (m, 4H), 2.10 (s, 3H), 2.31-2.47 (m, 5H), 3.50 (s, 2H),4.56-4.70 (m, 4H), 6.83-6.98 (m, 4H), 7.25-7.34 (m, 2H), 7.43-7.55 (m,2H).

Example 8(12)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(4-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.24 (28% aqueous ammonia:methanol=2:98);

NMR (CDCl₃): δ 1.53-1.65 (m, 6H), 2.20 (s, 3H), 2.30-2.44 (m, 6H),2.48-2.58 (m, 2H), 3.56 (s, 2H), 3.60 (s, 2H), 4.60-4.72 (m, 4H),6.68-6.71 (m, 1H), 6.74-6.79 (m, 1H), 6.95-7.09 (m, 4H), 7.32-7.39 (m,2H), 7.52-7.62 (m, 2H).

Example 8(13)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(4-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.24 (28% aqueous ammonia:methanol=2:98);

NMR (CDCl₃): δ 1.67-1.79 (m, 4H), 2.20 (s, 3H), 2.24-2.37 (m, 4H), 3.01(s, 4H), 3.42 (s, 2H), 3.73 (s, 2H), 4.58-4.71 (m, 4H), 6.66-6.71 (m,1H), 6.72-6.77 (m, 1H), 6.94-7.08 (m, 4H), 7.29-7.37 (m, 2H), 7.53-7.61(m, 2H).

Example 8(14)4-{[8-(3-hydroxypropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.20 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 1.47-1.84 (m, 8H), 2.34 (s, 2H), 2.36-2.72 (m, 8H), 3.59(s, 2H), 3.71-3.85 (m, 2H), 4.49-4.74 (m, 4H), 6.89-7.14 (m, 4H), 7.37(d, J=8.10 Hz, 2H), 7.65 (d, J=8.10 Hz, 2H).

Example 8(15)4-({[2-(1-cycloheptyl-4-piperidinyl)ethyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.15 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 1.13-1.92 (m, 19H), 2.14-2.33 (m, 2H), 2.48-2.69 (m, 3H),2.69-2.87 (m, 2H), 3.79 (s, 2H), 4.47-4.74 (m, 4H), 6.88-7.16 (m, 4H),7.35 (d, J=8.10 Hz, 2H), 7.63 (d, J=8.10 Hz, 2H).

Example 8(16)4-{[(1-cycloheptyl-4-piperidinyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.25 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 1.27-1.73 (m, 12H), 1.74-1.97 (m, 4H), 2.20-2.39 (m, 2H),2.40-2.54 (m, 1H), 2.54-2.71 (m, 1H), 2.73-2.92 (m, 2H), 3.81 (s, 2H),4.45-4.75 (m, 4H), 6.87-7.14 (m, 4H), 7.35 (d, J=8.10 Hz, 2H), 7.60 (d,J=8.10 Hz, 2H).

Example 8(17)N,N-bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)-4-({[trans-4-(dipropylamino)cyclohexyl]amino}methyl)benzamide

Description: amorphous;

TLC: Rf 0.41 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.79 (t, J=7.50 Hz, 6H), 0.89-1.05 (m, 2H), 1.06-1.21(m, 2H), 1.21-1.38 (m, 4H), 1.55-1.68 (m, 2H), 1.82-1.95 (m, 2H),2.14-2.41 (m, 6H), 2.56 (s, 6H), 2.90 (s, 6H), 3.68 (s, 2H), 4.82 (s,2H), 4.96 (s, 2H), 7.05 (d, J=1.50 Hz, 1H), 7.12 (d, J=1.50 Hz, 1H),7.25 (d, J=8.10 Hz, 2H), 7.32 (d, J=8.10 Hz, 2H), 7.51-7.61 (m, 2H).

Example 8(18)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)-3-methoxybenzamide

Description: amorphous;

TLC: Rf 0.76 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.04-1.35 (m, 6H), 1.56-1.69 (m, 6H), 1.76-1.98 (m, 4H),2.28-2.37 (m, 1H), 2.44 (s, 2H), 2.49-2.68 (m, 6H), 3.63 (s, 2H), 3.68(s, 3H), 4.49-4.88 (m, 4H), 6.91-7.21 (m, 6H), 7.33 (d, J=7.8 Hz, 1H).

Example 8(19)4-({[trans-4-(dipropylamino)-1-methylcyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.10 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 0.81-0.93 (m, 6H), 1.18 (s, 3H), 1.37-1.51 (m, 8H),1.67-1.81 (m, 4H), 2.41-2.56 (m, 5H), 3.77 (s, 2H), 4.53-4.68 (m, 4H),6.95-7.09 (m, 4H), 7.33-7.42 (m, 2H), 7.50-7.60 (m, 2H).

Example 8(20)4-{[[trans-4-(dipropylamino)-1-methylcyclohexyl](methyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.26 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 0.82-0.94 (m, 6H), 1.04 (s, 3H), 1.39-1.54 (m, 8H),1.73-1.88 (m, 4H), 2.05 (s, 3H), 2.44-2.58 (m, 5H), 3.53 (s, 2H),4.60-4.73 (m, 4H), 6.94-7.08 (m, 4H), 7.33-7.44 (m, 2H), 7.49-7.59 (m,2H).

Example 8(21)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(8-{[3-(methoxymethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.23 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.52-1.65 (m, 6H), 2.31-2.45 (m, 6H), 2.50-2.60 (m, 2H),3.32 (s, 3H), 3.57 (s, 2H), 3.63 (s, 2H), 4.40 (s, 2H), 4.58-4.71 (m,4H), 6.92-7.07 (m, 5H), 7.11-7.18 (m, 1H), 7.31-7.40 (m, 2H), 7.57-7.64(m, 2H).

Example 8(22)4-({8-[(3-chloro-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.21 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.52-1.66 (m, 6H), 2.35-2.49 (m, 6H), 2.52-2.63 (m, 2H),3.61 (s, 2H), 3.67 (s, 2H), 4.58-4.71 (m, 4H), 6.82-6.88 (m, 1H),6.94-7.08 (m, 4H), 7.17-7.23 (m, 1H), 7.33-7.41 (m, 2H), 7.59-7.66 (m,2H).

Example 8(23)4-({[2-(1-cycloheptyl-4-piperidinylidene)ethyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.28 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 1.27-1.91 (m, 12H), 2.11-2.33 (m, 4H), 2.40-2.73 (m, 5H),3.21 (d, J=6.9 Hz, 2H), 3.78 (s, 2H), 4.43-4.77 (m, 4H), 5.23 (t, J=6.9Hz, 1H), 6.85-7.12 (m, 4H), 7.34 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz,2H).

Example 8(24)N,N-bis(1H-imidazol-2-ylmethyl)-4-({[trans-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)cyclohexyl]amino}methyl)benzamide

Description: amorphous;

TLC: Rf 0.28 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.90-1.09 (m, 2H), 1.09-1.28 (m, 2H), 1.60-1.76 (m,2H), 1.82-1.98 (m, 2H), 2.03-2.15 (m, 4H), 2.16-2.31 (m, 2H), 2.33-2.46(m, 2H), 2.51-2.58 (m, 2H), 3.68 (s, 2H), 4.42-4.71 (m, 4H), 5.62-5.75(m, 2H), 6.75-7.16 (m, 4H), 7.30 (d, J=8.10 Hz, 2H), 7.39 (d, J=8.10 Hz,2H), 11.69-12.81 (m, 2H).

Example 8(25)N,N-bis(1H-imidazol-2-ylmethyl)-4-{8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}cyclohexanecarboxamide(low polar compound)

Description: amorphous;

TLC: Rf 0.57 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.22-2.60 (m, 19H), 2.18 (s, 3H), 2.86 (br-s, 2H),3.00-3.20 (m, 3H), 3.60 (s, 2H), 4.66 (br-s, 4H), 6.77 (d, J=5.4 Hz,1H), 7.00 (br-s, 2H), 7.03 (br-s, 2H), 7.12 (d, J=5.4 Hz, 1H).

Example 8(26)N,N-bis(1H-imidazol-2-ylmethyl)-4-{8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}cyclohexanecarboxamide(high polar compound)

Description: amorphous;

TLC: Rf 0.53 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.22-2.18 (m, 15H), 2.18 (s, 3H), 2.30-2.45 (m, 4H), 2.50(s, 2H), 2.65-2.75 (m, 3H), 3.57 (s, 2H), 4.61 (br-s, 2H), 4.73 (br-s,2H), 6.77 (d, J=5.1 Hz, 1H), 6.98 (br-s, 4H), 7.11 (d, J=5.1 Hz, 1H).

Example 8(27)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(2-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.57 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.50-1.63 (m, 6H), 2.33 (s, 3H), 2.33-2.40 (m, 6H), 2.56(t, J=6.9 Hz, 2H), 3.39 (s, 2H), 3.59 (s, 2H), 4.62 (br-s, 2H), 4.65(br-s, 2H), 6.99 (br-s, 2H), 7.06 (br-s, 2H), 7.13-7.26 (m, 4H), 7.38(d, J=8.1 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H).

Example 8(28)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(3-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.52 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.54-1.62 (m, 6H), 2.33 (m, 9H), 2.54 (t, J=6.9 Hz, 2H),3.41 (s, 2H), 3.57 (s, 2H), 4.63 (br-s, 4H), 6.99-7.21 (m, 8H), 7.37 (d,J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H).

Example 8(29)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(4-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.50 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.54-1.61 (m, 6H), 2.32 (m, 9H), 2.54 (t, J=6.9 Hz, 2H),3.41 (s, 2H), 3.57 (s, 2H), 4.63 (br-s, 4H), 7.00 (br-s, 2H), 7.07(br-s, 2H), 7.10 (d, J=7.8 Hz, 2H), 7.18 (d, J=7.8 Hz, 2H), 7.37 (d,J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H).

Example 8(30)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(2-methoxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.26 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.50-1.64 (m, 6H), 2.35-2.45 (m, 6H), 2.53 (t, J=7.8 Hz,2H), 3.51 (s, 2H), 3.57 (s, 2H), 3.80 (s, 3H), 4.62 (br-s, 4H), 6.85 (d,J=7.5 Hz, 1H), 6.91 (dt, J=7.5, 1.5 Hz, 1H), 7.00 (br-s, 2H), 7.07(br-s, 2H), 7.21 (dt, J=7.5, 1.5 Hz, 1H), 7.34 (dd, J=7.5, 1.5 Hz, 1H),7.38 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H).

Example 8(31)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(3-methoxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.26 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.54-1.64 (m, 6H), 2.30-2.40 (m, 6H), 2.55 (t, J=6.9 Hz,2H), 3.43 (s, 2H), 3.58 (s, 2H), 3.79 (s, 3H), 4.62 (br-s, 2H), 4.64(br-s, 2H), 6.77 (dd, J=8.1, 2.1 Hz, 1H), 6.87-6.89 (m, 2H), 6.98 (br-s,2H), 7.06 (br-s, 2H), 7.20 (t, J=8.1 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H),7.64 (d, J=8.1 Hz, 2H).

Example 8(32)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(4-methoxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.28 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.54-1.64 (m, 6H), 2.28-2.38 (m, 6H), 2.54 (t, J=6.9 Hz,2H), 3.39 (s, 2H), 3.57 (s, 2H), 3.79 (s, 3H), 4.63 (br-s, 4H), 6.83 (d,J=8.4 Hz, 2H), 7.00 (br-s, 2H), 7.07 (br-s, 2H), 7.20 (d, J=8.4 Hz, 2H),7.37 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H).

Example 8(33)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-(trifluoromethyl)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.52 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.56-1.65 (m, 6H), 2.38 (m, 6H), 2.57 (t, J=6.9 Hz, 2H),3.60 (s, 4H), 4.64 (br-s, 4H), 7.00 (br-s, 2H), 7.07 (br-s, 2H), 7.30(m, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.59 (d, J=7.5Hz, 1H), 7.66 (d, J=8.1 Hz, 2H), 7.80 (d, J=7.5 Hz, 1H).

Example 8(34)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[3-(trifluoromethyl)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.46 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.50-1.63 (m, 6H), 2.34 (m, 6H), 2.55 (t, J=6.9 Hz, 2H),3.48 (s, 2H), 3.58 (s, 2H), 4.63 (br-s, 4H), 7.00 (br-s, 2H), 7.08(br-s, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.43 (m, 1H), 7.48-7.51 (m, 2H),7.56 (m, 1H), 7.67 (d, J=8.1 Hz, 2H).

Example 8(35)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[4-(trifluoromethyl)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.41 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.56-1.67 (m, 6H), 2.35-2.42 (m, 6H), 2.62 (t, J=6.6 Hz,2H), 3.55 (s, 2H), 3.63 (s, 2H), 4.60 (br-s, 4H), 7.02 (br-s, 4H), 7.37(d, J=8.1 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 7.50 (d, J=7.8 Hz, 2H), 7.60(d, J=8.1 Hz, 2H).

Example 8(36)2,6-dichloro-N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.42 (ethyl acetate:methanol:28% aqueous ammonia=90:10:2);

NMR (CDCl₃): δ 1.48-1.68 (m, 6H), 2.17 (s, 3H), 2.25-2.50 (m, 6H), 2.53(t, J=6.9 Hz, 2H), 3.50 (s, 2H), 3.58 (s, 2H), 4.50 (s, 2H), 4.79 (s,2H), 6.75 (d, J=4.8 Hz, 1H), 6.95 (s, 2H), 7.03 (s, 2H), 7.09 (d, J=4.8Hz, 1H), 7.25 (s, 2H).

Example 8(37)4-{[[trans-4-(dipropylamino)cyclohexyl](methyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.21 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.80 (t, J=7.50 Hz, 6H), 1.06-1.42 (m, 8H), 1.63-1.75(m, 2H), 1.75-1.88 (m, 2H), 2.05 (s, 3H), 2.21-2.44 (m, 6H), 3.50 (s,2H), 4.45-4.70 (m, 4H), 6.68-7.19 (m, 4H), 7.27 (d, J=8.10 Hz, 2H), 7.41(d, J=8.10 Hz, 2H), 11.81-12.73 (m, 2H).

Example 8(38)4-{[[trans-4-(dipropylamino)cyclohexyl](ethyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.35 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.81 (t, J=7.20 Hz, 6H), 0.90 (t, J=6.90 Hz, 3H),1.13-1.50 (m, 8H), 1.63-1.90 (m, 4H), 2.22-2.48 (m, 8H), 3.52-3.63 (m,2H), 4.44-4.70 (m, 4H), 6.86-7.09 (m, 4H), 7.31 (d, J=8.10 Hz, 2H), 7.42(d, J=8.10 Hz, 2H), 11.83-12.80 (m, 2H).

Example 8(39)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(8-{[3-(trifluoromethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.37 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.56-1.67 (m, 6H), 2.35-2.49 (m, 6H), 2.52-2.63 (m, 2H),3.60 (s, 2H), 3.72 (s, 2H), 4.61-4.74 (m, 4H), 6.94-7.10 (m, 5H),7.15-7.24 (m, 1H), 7.31-7.40 (m, 2H), 7.50-7.59 (m, 2H).

Example 8(40)4-[(8-{[3-(hydroxymethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.53 (28% aqueous ammonia:methanol:chloroform=2:13:90);

NMR (CDCl₃): δ 1.52-1.66 (m, 6H), 2.34-2.50 (m, 6H), 2.53-2.64 (m, 2H),3.61 (s, 4H), 4.57 (s, 2H), 4.60-4.71 (m, 4H), 6.94-7.09 (m, 6H),7.32-7.44 (m, 2H), 7.59-7.70 (m, 2H).

Example 8(41)2-{[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-3-thiophenecarboxylicacid

Description: amorphous;

TLC: Rf 0.70 (28% aqueous ammonia:methanol:chloroform=5:15:35);

NMR (CD₃OD): δ 1.74-1.87 (m, 6H), 2.58 (s, 2H), 2.70-2.80 (m, 2H),3.03-3.17 (m, 4H), 3.74 (s, 2H), 4.38 (s, 2H), 4.61-4.78 (m, 4H), 7.03(s, 4H), 7.34-7.43 (m, 3H), 7.43-7.51 (m, 3H).

Example 8(42)2-{[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-3-thiophenecarboxamide

Description: amorphous;

TLC: Rf 0.45 (28% aqueous ammonia:methanol:chloroform=2:13:90);

NMR (CD₃OD): δ 1.54-1.68 (m, 6H), 2.34-2.50 (m, 6H), 2.52-2.65 (m, 2H),3.60 (s, 2H), 3.73 (s, 2H), 4.61-4.80 (m, 4H), 7.00 (s, 4H), 7.23-7.30(m, 1H), 7.33-7.41 (m, 3H), 7.43-7.51 (m, 2H).

Example 8(43)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(3-methoxy-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.23 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.51-1.65 (m, 6H), 2.31-2.46 (m, 6H), 2.49-2.58 (m, 2H),3.55 (s, 2H), 3.62 (s, 2H), 3.79 (s, 3H), 4.58-4.72 (m, 4H), 6.77-6.83(m, 1H), 6.89-7.04 (m, 4H), 7.07-7.14 (m, 1H), 7.29-7.38 (m, 2H),7.54-7.66 (m, 2H).

Example 8(44)4-({benzyl[trans-4-(dipropylamino)cyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.57 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.81 (t, J=7.50 Hz, 6H), 1.31 (m, 8H), 1.87 (m, 4H),2.37 (m, 6H), 3.57 (m, 4H), 4.54 (m, 4H), 6.97 (m, 4H), 7.22 (m, 7H),7.41 (d, J=8.10 Hz, 2H), 12.23 (m, 2H).

Example 8(45)4-[({trans-4-[(2-hydroxyethyl)(2-thienylmethyl)amino]cyclohexyl}amino)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.63 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.98-1.20 (m, 2H), 1.20-1.45 (m, 2H), 1.73-1.91 (m, 2H),1.92-2.12 (m, 2H), 2.30-2.47 (m, 1H), 2.50-2.66 (m, 1H), 2.69 (t, J=5.40Hz, 2H), 3.41-3.57 (m, 2H), 3.80 (s, 2H), 3.84 (s, 2H), 4.49-4.75 (m,4H), 6.87 (dd, J=3.60, 1.20 Hz, 1H), 6.92 (dd, J=5.10, 3.60 Hz, 1H),6.94-7.11 (m, 4H), 7.20 (dd, J=5.10, 1.20 Hz, 1H), 7.34 (d, J=8.40 Hz,2H), 7.58 (d, J=8.40 Hz, 2H).

Example 8(46)4-[({trans-4-[(3-hydroxypropyl)(2-thienylmethyl)amino]cyclohexyl}amino)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.63 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.96-1.22 (m, 2H), 1.22-1.47 (m, 2H), 1.60-1.77 (m, 2H),1.76-1.92 (m, 2H), 1.91-2.11 (m, 2H), 2.28-2.48 (m, 1H), 2.56-2.80 (m,3H), 3.66-3.90 (m, 6H), 4.50-4.75 (m, 4H), 6.87-6.96 (m, 2H), 6.96-7.11(m, 4H), 7.21 (dd, J=4.8, 1.5 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.60 (d,J=8.1 Hz, 2H).

Example 8(47)4-{[(trans-4-{(2-hydroxyethyl)[(3-methyl-2-thienyl)methyl]amino}cyclohexyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.64 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.97-1.21 (m, 2H), 1.21-1.47 (m, 2H), 1.72-1.91 (m, 2H),1.92-2.10 (m, 2H), 2.16 (s, 3H), 2.30-2.50 (m, 1H), 2.48-2.76 (m, 3H),3.39-3.56 (m, 2H), 3.73 (s, 2H), 3.80 (s, 2H), 4.48-4.76 (m, 4H), 6.77(d, J=5.1 Hz, 1H), 6.87-7.07 (m, 4H), 7.09 (d, J=5.1 Hz, 1H), 7.34 (d,J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H).

Example 8(48)4-{[(trans-4-{(3-hydroxypropyl)[(3-methyl-2-thienyl)methyl]amino}cyclohexyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.69 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.97-1.22 (m, 2H), 1.22-1.49 (m, 2H), 1.58-1.75 (m, 2H),1.75-1.92 (m, 2H), 1.92-2.10 (m, 2H), 2.18 (s, 3H), 2.29-2.48 (m, 1H),2.55-2.79 (m, 3H), 3.60-3.77 (m, 4H), 3.81 (s, 2H), 4.49-4.73 (m, 4H),6.77 (d, J=5.10 Hz, 1H), 6.92-7.10 (m, 4H), 7.12 (d, J=5.10 Hz, 1H),7.36 (d, J=8.10 Hz, 2H), 7.65 (d, J=8.10 Hz, 2H).

Example 8(49)N,N-bis(1H-imidazol-2-ylmethyl)-4-[({trans-4-[propyl(2-thienylmethyl)amino]cyclohexyl}amino)methyl]benzamide

Description: amorphous;

TLC: Rf 0.64 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.85 (t, J=7.20 Hz, 3H), 0.97-1.55 (m, 6H), 1.72-1.91 (m,2H), 1.91-2.09 (m, 2H), 2.29-2.64 (m, 4H), 3.69-3.90 (m, 4H), 4.48-4.77(m, 4H), 6.85 (dd, J=3.30, 1.20 Hz, 1H), 6.91 (dd, J=5.10, 3.30 Hz, 1H),6.93-7.10 (m, 4H), 7.16 (dd, J=5.10, 1.20 Hz, 1H), 7.33 (d, J=8.10 Hz,2H), 7.55 (d, J=8.10 Hz, 2H).

Example 8(50)N,N-bis(1H-imidazol-2-ylmethyl)-4-[({trans-4-[[(3-methyl-2-thienyl)methyl](propyl)amino]cyclohexyl}amino)methyl]benzamide

Description: amorphous;

TLC: Rf 0.67 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 0.85 (t, J=7.20 Hz, 3H), 0.98-1.19 (m, 2H), 1.20-1.53 (m,4H), 1.72-1.91 (m, 2H), 1.91-2.08 (m, 2H), 2.15 (s, 3H), 2.29-2.65 (m,4H), 3.66 (s, 2H), 3.80 (s, 2H), 4.48-4.78 (m, 4H), 6.75 (d, J=5.10 Hz,1H), 6.91-7.12 (m, 5H), 7.34 (d, J=8.10 Hz, 2H), 7.56 (d, J=8.10 Hz,2H).

Example 8(51)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[(trans-4-{[(3-methyl-2-thienyl)methyl]amino}cyclohexyl)amino]methyl}benzamide

Description: amorphous;

TLC: Rf 0.53 (methanol:28% aqueous ammonia=98:2);

NMR (CDCl₃): δ 1.01-1.30 (m, 4H), 1.84-2.08 (m, 4H), 2.18 (s, 3H),2.36-2.64 (m, 2H), 3.82 (s, 2H), 3.90 (s, 2H), 4.46-4.78 (m, 4H), 6.79(d, J=5.10 Hz, 1H), 6.92-7.07 (m, 4H), 7.08 (d, J=5.10 Hz, 1H), 7.35 (d,J=8.10 Hz, 2H), 7.58 (d, J=8.10 Hz, 2H).

Example 8(52)4-(2-{[4-(dipropylamino)cyclohexyl]amino}ethyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.63 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 0.82 (t, J=7.2 Hz, 6H), 1.25-1.46 (m, 10H), 1.65-1.74 (m,2H), 2.34-2.45 (m, 5H), 2.72 (m, 1H), 2.79-2.83 (m, 4H), 4.58 (br-s,2H), 4.64 (br-s, 2H), 7.01 (br-s, 2H), 7.08 (br-s, 2H), 7.27 (d, J=8.4Hz, 2H), 7.66 (d, J=8.4 Hz, 2H).

Example 8(53)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(2-nitrobenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.60 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.52-1.61 (m, 6H), 2.26-2.36 (m, 6H), 2.54 (t, J=6.9 Hz,2H), 3.58 (s, 2H), 3.72 (s, 2H), 4.61 (br-s, 4H), 6.99 (br-s, 2H), 7.07(br-s, 2H), 7.35 (m, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.50 (m, 1H), 7.59 (d,J=8.1 Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.1 Hz, 1H).

Example 8(54)4-{[8-(2-cyanobenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.53 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.55-1.63 (m, 6H), 2.35-2.44 (m, 6H), 2.55 (t, J=6.9 Hz,2H), 3.59 (s, 2H), 3.64 (s, 2H), 4.63 (br-s, 4H), 7.02 (br-s, 2H), 7.09(br-s, 2H), 7.32 (m, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.53-7.55 (m, 2H),7.62 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H).

Example 8(55)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-(trifluoromethoxy)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.50 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.55-1.66 (m, 6H), 2.33-2.40 (m, 6H), 2.55 (t, J=6.9 Hz,2H), 3.52 (s, 2H), 3.58 (s, 2H), 4.67 (br-s, 2H), 4.71 (br-s, 2H), 7.01(br-s, 2H), 7.04 (br-s, 2H), 7.20-7.26 (m, 3H), 7.35 (d, J=8.1 Hz, 2H),7.50 (d, J=8.0 Hz, 2H), 7.56 (m, 1H).

Example 8(56)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-(methylthio)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.51 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.54-1.63 (m, 6H), 2.35-2.42 (m, 6H), 2.43 (s, 3H), 2.54(t, J=6.9 Hz, 2H), 3.50 (s, 2H), 3.57 (s, 2H), 4.67 (br-s, 2H), 4.72(br-s, 2H), 6.99 (br-s, 2H), 7.04 (br-s, 2H), 7.09 (m, 1H), 7.21-7.23(m, 2H), 7.31 (m, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H).

Example 8(57)4-{[8-(2-hydroxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.55 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.58-1.66 (m, 6H), 2.33-2.37 (m, 6H), 2.56 (t, J=6.9 Hz,2H), 3.57 (s, 2H), 3.66 (s, 2H), 4.67 (br-s, 2H), 4.71 (br-s, 2H),6.73-6.81 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 7.00 (br-s, 2H), 7.05 (br-s,2H), 7.15 (m, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H).

Example 8(58)4-({[2-(4-cyclohexyl-1-piperazinyl)-2-oxoethyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.83 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.05-1.35 (m, 5H), 1.57-1.68 (m, 1H), 1.73-1.91 (m, 4H),2.22-2.38 (m, 1H), 2.52-2.61 (m, 4H), 3.39-3.44 (m, 2H), 3.45 (s, 2H),3.52-3.60 (m, 2H), 3.78 (s, 2H), 4.50-4.81 (m, 4H), 7.02 (s, 4H), 7.39(d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H).

Example 8(59)4-({8-[(3-fluoro-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.20 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.51-1.65 (m, 6H), 2.31-2.45 (m, 6H), 2.51-2.62 (m, 2H),3.54-3.65 (m, 4H), 4.61-4.72 (m, 4H), 6.71-6.75 (m, 1H), 6.93-7.04 (m,4H), 7.06-7.10 (m, 1H), 7.30-7.38 (m, 2H), 7.55-7.60 (m, 2H).

Example 8(60)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(5-nitro-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.11 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.55-1.68 (m, 6H), 2.35-2.49 (m, 6H), 2.51-2.65 (m, 2H),3.55-3.67 (m, 4H), 4.62-4.76 (m, 4H), 6.76-6.86 (m, 1H), 6.90-7.04 (m,4H), 7.29-7.39 (m, 2H), 7.48-7.60 (m, 2H), 7.71-7.84 (m, 1H).

Example 8(61)4-{[[trans-4-(dipropylamino)cyclohexyl](1H-imidazol-2-ylmethyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.67 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (DMSO-d₆): δ 0.78 (t, J=7.20 Hz, 6H), 1.07 (m, 2H), 1.29 (m, 6H),1.66 (m, 2H), 1.80 (m, 2H), 2.29 (m, 6H), 3.59 (m, 4H), 4.56 (m, 4H),6.72 (m, 1H), 6.97 (m, 5H), 7.38 (m, 4H), 11.59 (m, 1H), 12.27 (m, 2H).

Example 8(62)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.58 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.41-1.55 (m, 8H), 2.28-2.46 (m, 8H), 3.47 (s, 2H), 3.71(s, 2H), 4.62 (s, 2H), 4.66 (s, 2H), 6.88 (dd, J=3.6, 0.9 Hz, 1H), 6.93(dd, J=5.1, 3.6 Hz, 1H), 6.95 (s, 2H), 7.02 (s, 2H), 7.20 (dd, J=5.1,0.9 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H).

Example 8(63)N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.52 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 1.46-1.81 (m, 6H), 2.17 (s, 3H), 2.31-2.48 (m, 6H), 2.56(t, J=6.6 Hz, 2H), 3.57 (s, 4H), 4.75 (s, 2H), 4.95 (s, 2H), 6.76 (d,J=5.1 Hz, 1H), 7.07 (s, 2H), 7.10 (d, J=5.1 Hz, 1H), 7.18-7.32 (m, 4H),7.37 (d, J=8.1 Hz, 2H), 11.04 (s, 1H), 12.10 (s, 1H).

Example 8(64)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.13 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.51-1.65 (m, 6H), 2.20 (s, 3H), 2.27-2.43 (m, 6H),2.57-2.67 (m, 2H), 3.46 (s, 2H), 3.70 (s, 2H), 4.60-4.74 (m, 4H),6.73-6.81 (m, 1H), 6.96-7.10 (m, 5H), 7.28-7.38 (m, 2H), 7.49-7.58 (m,2H).

Example 8(65)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.18 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.23-1.36 (m, 2H), 1.46-1.61 (m, 6H), 2.12-2.18 (m, 2H),2.22-2.29 (m, 2H), 2.31-2.43 (m, 4H), 3.43 (s, 2H), 3.61 (s, 2H),4.60-4.74 (m, 4H), 6.82-6.87 (m, 1H), 6.88-6.95 (m, 1H), 6.95-7.07 (m,4H), 7.15-7.21 (m, 1H), 7.28-7.36 (m, 2H), 7.47-7.56 (m, 2H).

Example 8(66)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.18 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.23-1.36 (m, 2H), 1.45-1.60 (m, 6H), 2.14-2.28 (m, 7H),2.31-2.42 (m, 4H), 3.44 (s, 2H), 3.50 (s, 2H), 4.60-4.74 (m, 4H),6.72-6.80 (m, 1H), 6.95-7.09 (m, 5H), 7.27-7.36 (m, 2H), 7.46-7.56 (m,2H).

Example 8(67)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.28 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.22-1.36 (m, 2H), 1.46-1.61 (m, 6H), 2.00-2.15 (m, 2H),2.27-2.43 (m, 6H), 3.39 (s, 2H), 3.66 (s, 2H), 4.60-4.75 (m, 4H),6.81-6.86 (m, 1H), 6.87-6.93 (m, 1H), 6.95-7.08 (m, 4H), 7.13-7.21 (m,1H), 7.28-7.38 (m, 2H), 7.46-7.60 (m, 2H).

Example 8(68)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.30 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.24-1.38 (m, 2H), 1.46-1.61 (m, 6H), 2.05-2.20 (m, 5H),2.27-2.43 (m, 6H), 3.41 (s, 2H), 3.57 (s, 2H), 4.60-4.75 (m, 4H),6.71-6.78 (m, 1H), 6.95-7.10 (m, 5H), 7.29-7.39 (m, 2H), 7.47-7.60 (m,2H).

Example 8(69)N,N-bis(1H-imidazol-2-ylmethyl)-4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.20 (28% aqueous ammonia:methanol:ethyl acetate=2:8:90);

NMR (CDCl₃): δ 1.49-1.62 (m, 2H), 1.88-2.02 (m, 2H), 2.17 (s, 3H),2.21-2.27 (m, 2H), 2.30-2.39 (m, 2H), 2.42-2.50 (m, 4H), 3.46-3.57 (m,4H), 3.66-3.77 (m, 2H), 4.60-4.74 (m, 4H), 6.73-6.80 (m, 1H), 6.96-7.11(m, 5H), 7.29-7.39 (m, 2H), 7.49-7.58 (m, 2H).

Example 8(70)4-[(8-{[3-(1-hydroxyethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.57 (28% aqueous ammonia:methanol:chloroform=2:13:90);

NMR (CDCl₃): δ 1.49-1.63 (m, 9H), 2.33-2.56 (m, 8H), 3.39-3.48 (m, 1H),3.56 (s, 2H), 3.70-3.80 (m, 1H), 4.57-4.70 (m, 4H), 4.85-4.93 (m, 1H),6.95-7.09 (m, 6H), 7.31-7.39 (m, 2H), 7.57-7.65 (m, 2H).

Example 8(71)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(3-methyl-2-thienyl)carbonyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.67 (ethyl acetate:methanol:28% aqueous ammonia=80:20:2);

NMR (CDCl₃): δ d 1.55-1.65 (m, 4H), 1.68 (t, J=7.2 Hz, 2H), 2.24 (s,3H), 2.40 (s, 2H), 2.60 (t, J=7.2 Hz, 2H), 3.42-3.60 (m, 4H), 3.60 (s,2H), 4.60-4.78 (m, 4H), 6.81 (d, J=4.8 Hz, 1H), 6.98-7.14 (m, 4H), 7.24(d, J=4.8 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H).

Example 8(72) Ethyl{(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]amino}acetate

Description: amorphous;

TLC: Rf 0.28 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.83 (t, J=7.50 Hz, 6H), 1.12 (t, J=7.20 Hz, 3H),1.18-1.62 (m, 8H), 1.71-1.96 (m, 4H), 2.23-2.75 (m, 6H), 3.28 (s, 2H),3.73 (s, 2H), 4.00 (q, J=6.90 Hz, 2H), 4.46-4.68 (m, 4H), 6.86-7.10 (m,4H), 7.34 (d, J=8.10 Hz, 2H), 7.42 (d, J=8.10 Hz, 2H), 11.41-13.06 (m,2H).

Example 8(73)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.45 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.73-1.92 (m, 4H), 2.32-2.67 (m, 8H), 3.58 (s, 2H), 3.79(s, 2H), 4.60-4.73 (m, 4H), 6.86-6.89 (m, 1H), 6.91 (dd, J=5.00, 3.50Hz, 1H), 6.95-7.10 (m, 4H), 7.19 (dd, J=5.00, 1.50 Hz, 1H), 7.34 (d,J=8.00 Hz, 2H), 7.55 (d, J=8.00 Hz, 2H).

Example 8(74)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.60 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.48-1.60 (m, 2H), 1.90-2.01 (m, 2H), 2.19 (s, 2H),2.32-2.41 (m, 4H), 2.49-2.58 (m, 2H), 3.43 (s, 2H), 3.67-3.72 (m, 4H),4.59-4.71 (m, 4H), 6.87-6.90 (m, 1H), 6.92 (dd, J=5.1, 3.6 Hz, 1H),6.97-7.10 (m, 4H), 7.20 (dd, J=5.1, 1.50 Hz, 1H), 7.36 (d, J=8.4 Hz,2H), 7.60 (d, J=8.4 Hz, 2H).

Example 8(75)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.61 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.46-1.59 (m, 2H), 1.90-2.01 (m, 2H), 2.17 (s, 3H),2.17-2.21 (m, 2H), 2.31-2.42 (m, 4H), 2.50-2.60 (m, 2H), 3.43 (s, 2H),3.59 (s, 2H), 3.67-3.74 (m, 2H), 4.59-4.71 (m, 4H), 6.76 (d, J=5.1 Hz,1H), 6.97-7.09 (m, 4H), 7.10 (d, J=5.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H),7.60 (d, J=8.1 Hz, 2H).

Example 8(76)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[2-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.59 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.70-1.76 (m, 4H), 2.22-2.36 (m, 4H), 3.03 (s, 4H), 3.43(s, 2H), 3.79 (s, 2H), 4.59-4.69 (m, 4H), 6.87-6.90 (m, 1H), 6.93 (dd,J=5.1, 3.6 Hz, 1H), 6.96-7.10 (m, 4H), 7.19 (dd, J=5.1, 1.5 Hz, 1H),7.35 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H).

Example 8(77)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.61 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.70-1.76 (m, 4H), 2.17 (s, 3H), 2.22-2.36 (m, 4H), 3.03(s, 4H), 3.43 (s, 2H), 3.70 (s, 2H), 4.59-4.68 (m, 4H), 6.78 (d, J=5.1Hz, 1H), 6.98-7.10 (m, 4H), 7.09 (d, J=5.1 Hz, 1H), 7.35 (d, J=8.4 Hz,2H), 7.62 (d, J=8.4 Hz, 2H).

Example 8(78)N,N-bis(1H-imidazol-2-ylmethyl)-4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[4.4]non-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.65 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.73-1.92 (m, 4H), 2.17 (s, 3H), 2.55 (d, 8H), 3.56 (d,J=14.1 Hz, 1H), 3.61 (d, J=14.1 Hz, 1H), 3.70 (s, 2H), 4.60-4.71 (m,4H), 6.76 (d, J=5.1 Hz, 1H), 6.96-7.07 (m, 4H), 7.08 (d, J=5.1 Hz, 1H),7.35 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H).

Example 8(79)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.64 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.43-1.53 (m, 8H), 2.18 (s, 3H), 2.31-2.38 (m, 4H),2.38-2.45 (m, 4H), 3.49 (s, 2H), 3.60 (s, 2H), 4.59-4.70 (m, 4H), 6.77(d, J=5.1 Hz, 1H), 6.97-7.09 (m, 4H), 7.11 (d, J=5.1 Hz, 1H), 7.36 (d,J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H).

Example 8(80)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[7-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.59 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.76 (t, J=5.4 Hz, 4H), 2.29-2.42 (m, 4H), 2.99 (s, 4H),3.63 (s, 2H), 3.65 (s, 2H), 4.57-4.69 (m, 4H), 6.86-6.89 (m, 1H), 6.92(dd, J=5.1, 3.6 Hz, 1H), 6.96-7.10 (m, 4H), 7.21 (dd, J=5.1, 0.9 Hz,1H), 7.31 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H).

Example 8(81)N,N-bis(1H-imidazol-2-ylmethyl)-4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.60 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.75 (t, J=5.4 Hz, 4H), 2.16 (s, 3H), 2.30-2.41 (m, 4H),3.00 (s, 4H), 3.54 (s, 2H), 3.63 (s, 2H), 4.58-4.69 (m, 4H), 6.76 (d,J=5.1 Hz, 1H), 6.96-7.10 (m, 4H), 7.10 (d, J=5.1 Hz, 1H), 7.31 (d, J=8.4Hz, 2H), 7.59 (d, J=8.4 Hz, 2H).

Example 8(82)4-{[8-(2-hydroxy-2-methylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.14 (s, 6H), 1.52-1.65 (m, 6H), 2.26 (s, 2H), 2.33 (s,2H), 2.44-2.60 (m, 6H), 3.57 (s, 2H), 4.60-4.73 (m, 4H), 6.95-7.10 (m,4H), 7.36 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H).

Example 8(83)4-{[8-(3-hydroxy-3-methylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.31 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20 (s, 6H), 1.50-1.65 (m, 8H), 2.20-2.61 (m, 10H), 3.56(s, 2H), 4.60-4.73 (m, 4H), 6.95-7.09 (m, 4H), 7.35 (d, J=8.1 Hz, 2H),7.56 (d, J=8.1 Hz, 2H).

Example 8(84)4-{[8-(4-hydroxy-4-methylpentyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.32 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.19 (s, 6H), 1.54-1.70 (m, 10H), 2.20-2.58 (m, 10H),3.56 (s, 2H), 4.60-4.75 (m, 4H), 6.94-7.10 (m, 4H), 7.35 (d, J=8.1 Hz,2H), 7.56 (d, J=8.1 Hz, 2H).

Example 8(85)N,N-bis(1H-imidazol-2-ylmethyl)-4-[({(3S)-1-[(3-methyl-2-thienyl)methyl]-3-piperidinyl}amino)methyl]benzamide

Description: amorphous;

TLC: Rf 0.33 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 1.18-1.37 (m, 1H), 1.42-1.61 (m, 1H), 1.61-1.88 (m, 2H),1.95-2.36 (m, 5H), 2.50-2.66 (m, 1H), 2.66-2.86 (m, 2H), 3.60 (s, 2H),3.77 (s, 2H), 4.56-4.75 (m, 4H), 6.77 (d, J=5.1 Hz, 1H), 6.97-7.09 (m,4H), 7.11 (d, J=5.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz,2H).

Example 8(86)4-{[8-(2-ethyl-2-hydroxybutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.36 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.83 (t, J=7.2 Hz, 6H), 1.33-1.48 (m, 4H), 1.52-1.65 (m,6H), 2.25 (s, 2H), 2.32 (s, 2H), 2.42-2.60 (m, 6H), 3.57 (s, 2H),4.63-4.75 (m, 4H), 6.94-7.10 (m, 4H), 7.35 (d, J=8.1 Hz, 2H), 7.51 (d,J=8.1 Hz, 2H).

Example 8(87)4-({8-[(1-hydroxycyclohexyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.33 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-1.71 (m, 16H), 2.25 (s, 2H), 2.31 (s, 2H), 2.41-2.60(m, 6H), 3.56 (s, 2H), 4.62-4.78 (m, 4H), 6.92-7.10 (m, 4H), 7.34 (d,J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H).

Example 8(88)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(1-propylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.32 (ethyl acetate:methanol: 28% aqueous ammonia=90:8:2);

NMR (CDCl₃): δ 0.82-0.94 (m, 6H), 1.13-1.22 (m, 2H), 1.26-1.34 (m, 4H),1.36-1.45 (m, 2H), 1.48-1.62 (m, 6H), 2.27-2.43 (m, 7H), 2.48-2.60 (m,2H), 3.58 (s, 2H), 4.59-4.73 (m, 4H), 6.95-7.10 (m, 4H), 7.32-7.42 (m,2H), 7.53-7.65 (m, 2H).

Example 8(89)4-({8-[2-hydroxy-1-(hydroxymethyl)ethyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.13 (chloroform:methanol:28% aqueous ammonia=90:13:2);

NMR (CDCl₃): δ 1.51-1.65 (m, 6H), 2.25 (s, 2H), 2.55-2.69 (m, 6H),2.74-2.85 (m, 1H), 3.51-3.62 (m, 6H), 4.56-4.69 (m, 4H), 6.95-7.08 (m,4H), 7.30-7.38 (m, 2H), 7.45-7.54 (m, 2H).

Example 8(90)4-{[8-(2-hydroxy-2-propylpentyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.36 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.89 (t, J=7.2 Hz, 6H), 1.19-1.43 (m, 8H), 1.48-1.65 (m,6H), 2.25 (s, 2H), 2.32 (s, 2H), 2.40-2.60 (m, 6H), 3.57 (s, 2H),4.62-4.75 (m, 4H), 6.95-7.10 (m, 4H), 7.35 (d, J=8.1 Hz, 2H), 7.52 (d,J=8.1 Hz, 2H).

Example 8(91)N,N-bis(1H-imidazol-2-ylmethyl)-4-({[(3S)-1-(1-propylbutyl)-3-piperidinyl]amino}methyl)benzamide

Description: amorphous;

TLC: Rf 0.35 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 0.87 (t, J=7.2 Hz, 6H), 1.08-1.53 (m, 10H), 1.54-1.79 (m,2H), 2.18-2.40 (m, 3H), 2.42-2.54 (m, 1H), 2.55-2.78 (m, 2H), 3.80 (s,2H), 4.56-4.75 (m, 4H), 6.93-7.10 (m, 4H), 7.36 (d, J=8.1 Hz, 2H), 7.51(d, J=8.1 Hz, 2H).

Example 8(92)4-{[(3S)-3-(dipropylamino)-1-piperidinyl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.34 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 0.83 (t, J=7.2 Hz, 6H), 1.08-1.28 (m, 1H), 1.29-1.58 (m,5H), 1.59-1.93 (m, 4H), 2.32-2.48 (m, 4H), 2.62-2.79 (m, 2H), 2.86-2.96(m, 1H), 3.44 (d, J=13.5 Hz, 1H), 3.55 (d, J=13.5 Hz, 1H), 4.58-4.78 (m,4H), 6.92-7.10 (m, 4H), 7.34 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H).

Example 8(93)4-{[[trans-4-(dipropylamino)cyclohexyl](2-hydroxyethyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.25 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.80 (t, J=7.2 Hz, 6H), 1.04-1.46 (m, 8H), 1.59-1.85(m, 4H), 2.17-2.45 (m, 8H), 3.22-3.30 (m, 2H), 3.60 (s, 2H), 4.23 (t,J=5.1 Hz, 1H), 4.49-4.65 (m, 4H), 6.76-7.18 (m, 4H), 7.32 (d, J=8.1 Hz,2H), 7.42 (d, J=8.1 Hz, 2H), 11.86-12.65 (m, 2H).

Example 8(94)4-{[[trans-4-(dipropylamino)cyclohexyl](3-hydroxypropyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.29 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.79 (t, J=7.2 Hz, 6H), 1.03-1.39 (m, 8H), 1.39-1.53(m, 2H), 1.58-1.84 (m, 4H), 2.17-2.45 (m, 8H), 3.23-3.31 (m, 2H), 3.55(s, 2H), 4.27-4.42 (m, 1H), 4.48-4.66 (m, 4H), 6.75-7.19 (m, 4H), 7.29(d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 11.85-12.62 (m, 2H).

Example 8(95)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanecarboxamide

Description: amorphous;

TLC: Rf 0.20 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.59-1.85 (m, 27H), 2.01-2.64 (m, 10H), 4.51-4.62 (m,2H), 4.64-4.74 (m, 2H), 6.62-7.41 (m, 4H), 11.78-13.36 (m, 2H).

Example 8(96)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-methoxy-1-(methoxymethyl)ethyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide

Description: amorphous;

TLC: Rf 0.49 (chloroform:methanol:28% aqueous ammonia=90:13:2);

NMR (CDCl₃): δ 1.51-1.65 (m, 6H), 2.39 (s, 2H), 2.50-2.64 (m, 6H),2.72-2.80 (m, 1H), 3.32 (s, 6H), 3.41-3.55 (m, 4H), 3.61 (s, 2H),4.61-4.76 (m, 4H), 6.97-7.08 (m, 4H), 7.32-7.41 (m, 2H), 7.53-7.61 (m,2H).

Example 8(97)4-{[9-(2-ethylbutyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.84 (t, J=7.2 Hz, 6H), 1.19-1.52 (m, 13H), 2.10 (d,J=6.6 Hz, 2H), 2.24-2.39 (m, 8H), 3.48 (s, 2H), 4.60-4.74 (m, 4H),6.94-7.10 (m, 4H), 7.35 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H).

Example 8(98)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.42-1.53 (m, 8H), 1.76 (m, 1H),2.05 (d, J=7.5 Hz, 2H), 2.24-2.42 (m, 8H), 3.48 (s, 2H), 4.60-4.75 (m,4H), 6.94-7.10 (m, 4H), 7.35 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H).

Example 8(99)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzamide

Description: amorphous;

TLC: Rf 0.16 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.42-1.67 (m, 10H), 1.71-1.81 (m, 2H), 2.30-2.51 (m, 9H),3.30-3.42 (m, 2H), 3.48 (s, 2H), 3.96-4.08 (m, 2H), 4.60-4.74 (m, 4H),6.95-7.10 (m, 4H), 7.35 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H).

Example 8(100)4-[(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.22 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.40-1.53 (m, 8H), 1.58-1.74 (m, 2H), 1.78-2.17 (m, 4H),2.19-2.40 (m, 8H), 2.67 (m, 1H), 3.48 (s, 2H), 4.60-4.72 (m, 4H),6.95-7.10 (m, 4H), 7.35 (d, J=7.8 Hz, 2H), 7.53 (d, J=7.8 Hz, 2H).

Example 8(101)

N,N-bis(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-2,9-diazaspiro[5.5]undec-2-yl)methyl]benzamideTLC: Rf 0.39 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.84 (d, J=6.59 Hz, 6H), 1.21-1.63 (m, 8H), 1.64-1.80 (m,1H), 1.99 (d, J=7.32 Hz, 2H), 2.04-2.41 (m, 8H), 3.42 (s, 2H), 4.56-4.71(m, 4H), 6.95-7.15 (m, 4H), 7.37 (d, J=8.42 Hz, 2H), 7.62 (d, J=8.42 Hz,2H), 9.83-11.12 (m, 1H), 11.78-12.90 (m, 1H).

Example 8(102)4-{[9-(cyclobutylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.19 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.37-1.59 (m, 8H), 1.60-2.45 (m, 16H), 2.53 (m, 1H), 3.48(s, 2H), 4.61-4.75 (m, 4H), 6.97-7.12 (m, 4H), 7.35 (d, J=8.1 Hz, 2H),7.56 (d, J=8.1 Hz, 2H).

Example 8(103)4-({9-[(3-chloro-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.33 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.42-1.54 (m, 8H), 2.30-2.40 (m, 4H), 2.41-2.50 (m, 4H),3.48 (s, 2H), 3.70 (s, 2H), 4.60-4.72 (m, 4H), 6.85 (d, J=5.1 Hz, 1H),6.94-7.10 (m, 4H), 7.20 (d, J=5.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.55(d, J=8.1 Hz, 2H).

Example 8(104)3-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=40:10:1);

NMR (CDCl₃): δ 1.01-1.32 (m, 6H), 1.48-2.00 (m, 10H), 2.16-2.32 (m, 1H),2.38-2.55 (m, 4H), 2.42 (s, 2H), 2.55-2.70 (m, 4H), 2.72-2.83 (m, 2H),4.55-4.86 (m, 4H), 6.90-7.10 (m, 4H), 7.22-7.37 (m, 4H), 10.49-12.72 (m,2H).

Example 8(105)4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)methyl]-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.65 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.43-1.61 (m, 2H), 1.65-1.84 (m,1H), 1.85-1.98 (m, 2H), 2.00-2.49 (m, 10H), 3.42 (s, 2H), 3.49 (s, 3H),3.66-3.75 (m, 2H), 3.79 (s, 3H), 4.66 (s, 2H), 4.83 (s, 2H), 6.80 (s,2H), 6.87-7.06 (m, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H).

Example 8(106)4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.58 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.50-1.64 (m, 6H), 1.67-1.85 (m,1H), 2.02 (d, J=7.2 Hz, 2H), 2.20-2.31 (m, 4H), 2.32 (s, 2H), 2.54 (t,J=6.9 Hz, 2H), 3.45 (s, 3H), 3.56 (s, 2H), 3.79 (s, 3H), 4.66 (s, 2H),4.85 (s, 2H), 6.79 (s, 2H), 6.88-7.07 (m, 2H), 7.31 (d, J=8.1 Hz, 2H),7.57 (d, J=8.1 Hz, 2H).

Example 8(107)4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.58 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.33-1.60 (m, 8H), 1.68-1.87 (m,1H), 2.05 (d, J=7.2 Hz, 2H), 2.21-2.46 (m, 8H), 3.33-3.59 (m, 5H), 3.79(s, 3H), 4.65 (s, 2H), 4.85 (s, 2H), 6.79 (s, 2H), 6.87-7.06 (m, 2H),7.30 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H).

Example 8(108)N-(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.58 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.88 (d, J=6.6 Hz, 6H), 1.48-1.63 (m, 2H), 1.64-1.83 (m,1H), 1.85-1.99 (m, 2H), 2.02-2.10 (m, 2H), 2.15-2.52 (m, 8H), 3.34-3.94(m, 7H), 4.50-4.83 (m, 4H), 6.89 (s, 1H), 6.98-7.19 (m, 3H), 7.30-7.65(m, 4H), 13.73-14.01 (m, 1H).

Example 8(109)N-(1H-imidazol-2-ylmethyl)-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.62 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.49-1.64 (m, 6H), 1.69-1.85 (m,1H), 2.02 (d, J=7.2 Hz, 2H), 2.21-2.31 (m, 4H), 2.32 (s, 2H), 2.53 (t,J=6.9 Hz, 2H), 3.33-3.62 (m, 3H), 3.86 (s, 2H), 4.50-4.82 (m, 4H), 6.88(s, 1H), 7.05 (s, 1H), 7.07-7.13 (m, 2H), 7.29-7.61 (m, 4H), 13.69-14.02(m, 1H).

Example 8(110)N-(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

Description: amorphous;

TLC: Rf 0.62 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.39-1.52 (m, 8H), 1.68-1.87 (m,1H), 2.05 (d, J=7.1 Hz, 2H), 2.21-2.40 (m, 8H), 3.34-3.51 (m, 3H), 3.86(s, 2H), 4.48-4.82 (m, 4H), 6.88 (s, 1H), 6.97-7.16 (m, 3H), 7.28-7.65(m, 4H), 13.67-14.03 (m, 1H).

Example 8(111)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(7-isobutyl-2,7-diazaspiro[3.5]non-2-yl)methyl]benzamide

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (d, J=6.59 Hz, 6H), 1.69-1.82 (m, 5H), 1.99 (d,J=7.32 Hz, 2H), 2.17-2.31 (m, 4H), 2.99 (s, 4H), 3.63 (s, 2H), 4.58-4.73(m, 4H), 6.95-7.13 (m, 4H), 7.31 (d, J=8.42 Hz, 2H), 7.54 (d, J=8.42 Hz,2H), 9.92-11.03 (m, 1H), 12.02-12.86 (m, 1H).

Example 8(112)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,7-diazaspiro[3.5]non-7-yl)methyl]benzamide

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (d, J=6.59 Hz, 6H), 1.50-1.66 (m, 1H), 1.67-1.75 (m,4H), 2.19-2.36 (m, 4H), 2.23 (d, J=6.96 Hz, 2H), 2.94 (s, 4H), 3.43 (s,2H), 4.58-4.74 (m, 4H), 6.90-7.15 (m, 4H), 7.34 (d, J=8.24 Hz, 2H), 7.55(d, J=8.24 Hz, 2H), 10.09-10.82 (m, 1H), 12.21-12.87 (m, 1H).

Example 8(113)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,8-diazaspiro[4.5]dec-8-yl)methyl]benzamide

TLC: Rf 0.35 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.88 (d, J=6.59 Hz, 6H), 1.46-1.78 (m, 7H), 2.13 (d,J=7.32 Hz, 2H), 2.24-2.40 (m, 4H), 2.28 (s, 2H), 2.49 (t, J=6.87 Hz,2H), 3.46 (s, 2H), 4.58-4.77 (m, 4H), 6.95-7.16 (m, 4H), 7.35 (d, J=8.42Hz, 2H), 7.54 (d, J=8.42 Hz, 2H), 10.09-10.79 (m, 1H), 12.12-12.88 (m,1H).

Example 8(114)4-{[2-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.40 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (s, 9H), 1.44-1.65 (m, 6H), 2.16 (s, 2H), 2.22-2.40(m, 4H), 2.43 (s, 2H), 2.63 (t, J=6.96 Hz, 2H), 3.46 (s, 2H), 4.57-4.76(m, 4H), 6.94-7.16 (m, 4H), 7.35 (d, J=8.24 Hz, 2H), 7.49-7.60 (m,J=8.24 Hz, 2H), 9.91-10.99 (m, 1H), 11.99-13.03 (m, 1H).

Example 8(115)4-{[2-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.41 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.85 (t, J=7.4 Hz, 6H), 1.31-1.65 (m, 10H), 1.92-2.05 (m,1H), 2.24-2.43 (m, 4H), 2.38 (s, 2H), 2.58 (t, J=6.9 Hz, 2H), 3.46 (s,2H), 4.55-4.74 (m, 4H), 6.93-7.14 (m, 4H), 7.36 (d, J=8.2 Hz, 2H), 7.59(d, J=8.2 Hz, 2H).

Example 8(116)4-{[9-(1-ethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.46 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.83 (t, J=7.3 Hz, 6H), 1.12-1.63 (m, 12H), 2.00-2.15 (m,3H), 2.22-2.49 (m, 6H), 3.42 (s, 2H), 4.55-4.74 (m, 4H), 6.95-7.14 (m,4H), 7.37 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H).

Example 8(117)4-{[9-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.59 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.81 (s, 9H), 1.20-1.63 (m, 8H), 1.95 (s, 2H), 2.03-2.14(m, 2H), 2.21-2.47 (m, 6H), 3.42 (s, 2H), 4.56-4.73 (m, 4H), 6.93-7.15(m, 4H), 7.36 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 9.98-11.02 (m,1H), 11.88-12.89 (m, 1H).

Example 8(118)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(4-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)methyl]benzamide

TLC: Rf 0.46 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (d, J=6.4 Hz, 6H), 1.47-2.03 (m, 5H), 1.98 (d, J=7.3Hz, 2H), 2.16 (s, 2H), 2.26-2.54 (m, 6H), 3.50 (s, 2H), 3.62-3.76 (m,2H), 4.50-4.76 (m, 4H), 6.91-7.19 (m, 4H), 7.37 (d, J=8.2 Hz, 2H), 7.61(d, J=8.2 Hz, 2H), 9.88-11.07 (m, 1H), 11.98-12.96 (m, 1H).

Example 8(119)4-{[4-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.50 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.87 (t, J=7.3 Hz, 6H), 1.15-1.63 (m, 6H), 1.74-2.12 (m,3H), 2.27-2.52 (m, 8H), 3.50 (s, 2H), 3.62-3.70 (m, 2H), 4.57-4.72 (m,4H), 6.95-7.12 (m, 4H), 7.37 (d, J=8.2 Hz, 2H), 7.57-7.65 (m, J=8.2 Hz,2H), 9.78-10.92 (m, 1H), 11.82-13.17 (m, 1H).

Example 8(120)4-{[2-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.42 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.83 (s, 9H), 1.65-1.76 (m, 4H), 2.18 (s, 2H), 2.20-2.37(m, 4H), 2.98 (s, 4H), 3.42 (s, 2H), 4.57-4.77 (m, 4H), 6.93-7.13 (m,4H), 7.33 (d, J=8.2 Hz, 2H), 7.43-7.55 (m, J=8.2 Hz, 2H), 9.97-10.84 (m,1H), 12.01-12.97 (m, 1H).

Example 8(121)4-{[2-(1-ethylpropyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.41 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.81 (t, J=7.4 Hz, 6H), 1.21-1.44 (m, 4H), 1.67-1.75 (m,4H), 1.92-2.03 (m, 1H), 2.23-2.37 (m, 4H), 2.93 (s, 4H), 3.43 (s, 2H),4.59-4.74 (m, 4H), 6.95-7.11 (m, 4H), 7.34 (d, J=8.2 Hz, 2H), 7.55 (d,J=8.2 Hz, 2H), 10.04-10.97 (m, 1H), 12.04-12.94 (m, 1H).

Example 8(122)4-{[7-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.39 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.83 (s, 9H), 1.65-1.75 (m, 4H), 1.96 (s, 2H), 2.30-2.42(m, 4H), 2.98 (s, 4H), 3.63 (s, 2H), 4.53-4.76 (m, 4H), 6.91-7.15 (m,4H), 7.31 (d, J=8.4 Hz, 2H), 7.50-7.62 (m, J=8.4 Hz, 2H), 10.11-11.11(m, 1H), 11.97-13.06 (m, 1H).

Example 8(123)4-{[7-(1-ethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.36 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (t, J=7.4 Hz, 6H), 1.15-1.54 (m, 4H), 1.65-1.74 (m,4H), 2.01-2.17 (m, 1H), 2.31-2.42 (m, 4H), 2.99 (s, 4H), 3.64 (s, 2H),4.52-4.71 (m, 4H), 6.95-7.15 (m, 4H), 7.33 (d, J=7.9 Hz, 2H), 7.66 (d,J=7.9 Hz, 2H).

Example 8(124)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,9-diazaspiro[5.5]undec-9-yl)methyl]benzamide

TLC: Rf 0.36 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.85 (d, J=6.6 Hz, 6H), 1.17-1.64 (m, 8H), 1.64-1.82 (m,1H), 1.95 (d, J=7.3 Hz, 2H), 1.99-2.49 (m, 8H), 3.48 (s, 2H), 4.47-4.77(m, 4H), 6.89-7.18 (m, 4H), 7.38 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.2 Hz,2H).

Example 8(125)4-{[2-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.83 (s, 9H), 1.13-1.67 (m, 8H), 1.94 (s, 2H), 2.16-2.47(m, 8H), 3.48 (s, 2H), 4.54-4.70 (m, 4H), 6.95-7.15 (m, 4H), 7.38 (d,J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H).

Example 8(126)4-{[2-(1-ethylpropyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.45 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (t, J=7.3 Hz, 6H), 1.08-1.64 (m, 12H), 1.98-2.12 (m,1H), 2.18-2.50 (m, 8H), 3.49 (s, 2H), 4.51-4.71 (m, 4H), 6.92-7.18 (m,4H), 7.38 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H).

Example 8(127)4-{[9-(2,2-dimethylpropyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.49 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.83 (s, 9H), 1.34-1.55 (m, 8H), 2.00 (s, 2H), 2.25-2.50(m, 8H), 3.47 (s, 2H), 4.54-4.81 (m, 4H), 6.88-7.17 (m, 4H), 7.34 (d,J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H).

Example 8(128)4-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.98-1.34 (m, 6H), 1.49-2.10 (m, 10H), 2.16-2.32 (m, 1H),2.40 (s, 2H), 2.44-2.55 (m, 4H), 2.54-2.67 (m, 4H), 2.74-2.86 (m, 2H),4.53-4.78 (m, 4H), 6.94-7.15 (m, 4H), 7.24 (d, J=8.1 Hz, 2H), 7.51 (d,J=8.1 Hz, 2H), 10.26-10.83 (m, 1H), 12.29-12.85 (m, 1H).

Example 9 Tert-butyl4-[({[bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl)methyl]amino}carbonyl)amino]methyl}piperidine-1-carboxylate

Under an argon atmosphere, to an anhydrous tetrahydrofuran (25 mL)solution of trichloromethyl 3,3,3-trichloro-2-oxopropanoic acid (519mg), triethylamine (4.9 mL) and an anhydrous tetrahydrofuran (5 mL)solution of the compound (1.53 g) obtained in Example 3 weresequentially added at −40° C. After the reaction solution was stirred at0° C. for one hour, an anhydrous tetrahydrofuran (5 mL) solution oftert-butyl 4-(aminomethyl)piperidine-1-carboxylate (750 mg) was added at0° C. The reaction solution was stirred at room temperature for 6 hours.To the reaction solution, an aqueous saturated sodium hydrogen carbonatesolution (50 mL) was added, followed by stirring for 5 minutes. Theaqueous layer was extracted twice with ethyl acetate (50 mL). Thecombined organic layer was washed with saturated brine and then driedover anhydrous magnesium sulfate. After removing the anhydrous sodiumsulfate by filtration, the filtrate was concentrated. Without purifyingthe residue, the title compound (3.03 g) having the following physicalproperties was obtained.

TLC: Rf 0.37 (chloroform:methanol=9:1).

Example 10 N,N-bis(1H-imidazol-2-ylmethyl)-N′-(piperidin-4-ylmethyl)urea

To the compound (3.00 g) obtained in Example 9, 4N hydrogenchloride/dioxane (15 mL) was added. The reaction solution was stirred at60° C. for 15 hours. The reaction solution was concentrated underreduced pressure. The residue was dissolved in methanol (20 mL) and acarbonate resin (trade name: MP-Carbonate, manufactured by Argonaut Co.,product number: 800267, 10 g) was added, followed by stirring at roomtemperature for 3 hours. After the resin was removed by filtration, thefiltrate was concentrated under reduced pressure. The title compound wasobtained without purifying the residue.

Example 11N′-({1-[4-(dipropylamino)butyl]-4-piperidinyl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)urea

Under an argon atmosphere, to a methanol (2.3 mL) solution of thecompound (73 mg) obtained in Example 10, 4-(dipropylamino)butanal (39mg) and trimethyl orthoformate (49 mg) were added at 0° C. The reactionsolution was stirred at room temperature for 2 hours. To the reactionsolution, sodium borohydride (17 mg) was added at 0° C., followed bystirring for one hour. The reaction solution was concentrated underreduced pressure, and then an aqueous 5N sodium hydroxide solution (10mL) was added to the residue. The aqueous layer was extracted twice withchloroform (30 mL). The combined organic layer was dried over anhydrousmagnesium sulfate. After removing the anhydrous sodium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (dichrolomethane:methanol:28% aqueousammonia=10:1:0→80:10:1) to obtain the title compound (37 mg) having thefollowing physical properties.

TLC: Rf 0.39 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 0.92 (t, J=7.50 Hz, 6H), 1.04-1.35 (m, 2H), 1.38-1.74 (m,11H), 1.95-2.12 (m, 2H), 2.30-2.48 (m, 2H), 2.49-2.69 (m, 6H), 2.89-3.11(m, 4H), 4.55 (s, 4H), 6.95-7.03 (m, 4H).

Example 11(1) to Example 11(11)

The same operation as in Example 9→Example 10→Example 11 was performed,except for using corresponding amine in place of tert-butyl4-(aminomethyl)piperidine-1-carboxylate in Example 9 and correspondingaldehyde in place of 4-(dipropylamino)butanal in Example 11, to obtainthe following compound.

Example 11(1)N′-{1-[(1-cycloheptyl-4-piperidinyl)methyl]-4-piperidinyl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)urea

Description: amorphous;

TLC: Rf 0.78 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.09-1.32 (m, 4H), 1.38-1.61 (m, 12H), 1.63-1.81 (m, 4H),1.81-1.93 (m, 4H), 2.16 (d, J=6.9 Hz, 2H), 2.27-2.42 (m, 2H), 2.53-2.68(m, 1H), 2.73-2.91 (m, 4H), 3.03 (d, J=6.6 Hz, 2H), 4.55 (s, 4H), 6.98(s, 4H).

Example 11(2)N′-{trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}-N,N-bis(1H-imidazol-2-ylmethyl)urea

Description: amorphous;

TLC: Rf 0.62 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 0.85-0.96 (m, 2H), 1.08-1.36 (m, 8H), 1.56-2.00 (m, 14H),2.17 (d, J=6.9 Hz, 2H), 2.30 (s, 2H), 2.48-2.52 (m, 4H), 2.60-2.71 (m,4H), 3.41 (m, 1H), 4.58 (br-s, 4H), 6.11 (m, 1H), 6.95 (br-s, 4H).

Example 11(3)N′-[4-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)cyclohexyl]-N,N-bis(1H-imidazol-2-ylmethyl)urea

Description: amorphous;

TLC: Rf 0.20 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.12-1.51 (m, 8H), 1.69-1.99 (m, 16H), 2.25 (br-s, 2H),2.52-2.81 (m, 8H), 3.79 (m, 1H), 4.61 (br-s, 4H), 6.12 (d, J=6.6 Hz,1H), 6.96 (br-s, 4H).

Example 11(4)N,N-bis(1H-imidazol-2-ylmethyl)-N′-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}urea

Description: amorphous;

TLC: Rf 0.38 (ethyl acetate:methanol:28% aqueous ammonia=80:10:2);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.49-1.65 (m, 6H), 1.68-1.83 (m,1H), 2.01 (d, J=7.2 Hz, 2H), 2.21-2.30 (m, 4H), 2.31 (s, 2H), 2.53 (t,J=6.9 Hz, 2H), 3.51 (s, 2H), 4.72 (s, 4H), 6.91 (s, 4H), 7.21 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 8.73 (s, 1H).

Example 11(5)N,N-bis(1H-imidazol-2-ylmethyl)-N′-(4-{[8-(2-thienylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}phenyl)urea

Description: amorphous;

TLC: Rf 0.38 (ethyl acetate:methanol:28% aqueous ammonia=80:10:2);

NMR (CDCl₃): δ 1.51-1.64 (m, 6H), 2.32 (s, 2H), 2.33-2.43 (m, 4H), 2.53(t, J=6.9 Hz, 2H), 3.51 (s, 2H), 3.67 (s, 2H), 4.73 (s, 4H), 6.84-6.98(m, 6H), 7.17-7.34 (m, 5H), 8.69 (s, 1H).

Example 11(6)N,N-bis(1H-imidazol-2-ylmethyl)-N′-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]urea

Description: amorphous;

TLC: Rf 0.39 (ethyl acetate:methanol:28% aqueous ammonia=80:10:2);

NMR (CDCl₃): δ 1.48-1.66 (m, 6H), 2.17 (s, 3H), 2.32 (s, 2H), 2.34-2.45(m, 4H), 2.53 (t, J=6.9 Hz, 2H), 3.51 (s, 2H), 3.56 (s, 2H), 4.73 (s,4H), 6.77 (d, J=4.8 Hz, 1H), 6.82-7.00 (m, 4H), 7.11 (d, J=4.8 Hz, 1H),7.21 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 8.72 (s, 1H).

Example 11(7)N′-[4-({[trans-4-(dipropylamino)cyclohexyl]amino}methyl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)urea

Description: amorphous;

TLC: Rf 0.56 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.84 (t, J=7.2 Hz, 6H), 1.05-1.47 (m, 8H), 1.72-1.84 (m,2H), 1.96-2.03 (m, 2H), 2.33-2.54 (m, 6H), 3.74 (s, 2H), 4.71 (s, 4H),6.92 (s, 4H), 7.19 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 8.73 (s,1H).

Example 11(8)N′-[4-({[4-(dipropylamino)butyl]amino}methyl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)urea

Description: amorphous;

TLC: Rf 0.58 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.86 (t, J=7.2 Hz, 6H), 1.33-1.54 (m, 8H), 2.26-2.46 (m,6H), 2.61 (t, J=6.6 Hz, 2H), 3.72 (s, 2H), 4.72 (s, 4H), 6.91 (s, 4H),7.20 (d, =8.7 Hz, 2H), 7.29 (d, =8.7 Hz, 2H), 8.75 (s, 1H).

Example 11(9)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N,N′-bis(1H-imidazol-2-ylmethyl)urea

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.00-1.32 (m, 6H), 1.50-1.70 (m, 6H), 1.70-1.90 (m, 4H),2.24 (m, 1H), 2.34 (s, 2H), 2.40-2.60 (m, 6H), 3.53 (s, 2H), 4.28-4.30(m, 2H), 4.40-4.52 (m, 4H), 6.71 (m, 1H), 6.86 (s, 2H), 6.91 (s, 2H),7.06 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H).

Example 11(10)N′-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)urea

Description: amorphous;

TLC: Rf 0.36 (ethyl acetate:methanol:28% aqueous ammonia=80:10:2);

NMR (CDCl₃): δ 0.95-1.92 (m, 16H), 2.11-2.28 (m, 1H), 2.31 (s, 2H),2.40-2.50 (m, 4H), 2.53 (t, J=6.9 Hz, 2H), 3.51 (s, 2H), 4.74 (s, 4H),6.89 (s, 4H), 7.21 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 8.65 (s,1H), 10.53-12.50 (m, 2H).

Example 11(11)4-({8-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.14 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.48-1.65 (m, 6H), 2.23-2.46 (m, 9H), 2.48-2.58 (m, 2H),2.61 (s, 3H), 3.51 (s, 2H), 3.57 (s, 2H), 4.60-4.78 (m, 4H), 6.96-7.12(m, 4H), 7.35 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H).

Example 121-[4-(diethoxymethyl)phenyl]-N-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]methanamine

With 4-(diethoxymethy)benzaldehyde (957 mg) and1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methanamine(1.05 g), the same operation as in Example 2 was performed to obtain thetitle compound (2.05 g) having the following physical properties.

TLC: Rf 0.63 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 7.43 (d, J=7.8 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H), 6.97 (m,2H), 5.49 (s, 1H), 5.32 (s, 2H), 3.94 (s, 2H), 3.84 (s, 2H), 3.52 (m,6H), 1.24 (m, 6H), 0.88 (m, 2H), −0.03 (s, 9H).

Example 13 Benzyl[4-(diethoxymethyl)benzyl][(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]carbamate

To a dichloromethane (30 mL) solution of compound (3.65 g) obtained inExample 12 and triethylamine (2.64 g), benzyl chloroformate (2.97 g) wasadded at 0° C. The reaction solution was stirred at 0° C. for 4 hours.To the reaction solution, an aqueous 1N sodium hydroxide solution (100mL) was added. The aqueous layer was extracted twice withdichloromethane (100 mL). The combined organic layer was washed withsaturated brine and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous sodium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(n-hexane:ethyl acetate=1:0→0:1) to obtain the title compound (1.80 g)having the following physical properties.

TLC: Rf 0.16 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.32 (m, 9H), 7.09 (m, 1H), 7.01 (m, 1H), 5.45 (s, 2H),5.41 (s, 1H), 5.20 (s, 2H), 4.74 (m, 4H), 3.58 (m, 6H), 1.27 (m, 6H),0.90 (m, 2H), −0.02 (s, 9H).

Example 14 Benzyl (4-formylbenzyl)(1H-imidazol-2-ylmethyl)carbamate

A 50% trifluoroacetic acid/dichloromethane (12 mL) solution of thecompound (1.79 g) obtained in Example 13 was stirred at room temperaturefor 8 hours. The reaction solution was concentrated under reducedpressure. To the residue, an aqueous 2N sodium hydroxide solution (75mL) was added. The aqueous layer was extracted twice withdichloromethane (100 mL). The combined organic layer was washed withsaturated brine and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous sodium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(n-hexane:ethyl acetate=3:1→10:1) to obtain the title compound (875 mg)having the following physical properties.

TLC: Rf 0.38 (ethyl acetate);

NMR (CDCl₃): δ 9.99 (s, 1H), 7.80 (m, 2H), 7.28 (m, 7H), 6.99 (m, 2H),5.20 (s, 2H), 4.62 (s, 2H), 4.46 (s, 2H).

Example 15 Benzyl{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)carbamate

The same operation as in Example 2 was performed, except for using thecompound (643 mg) obtained in Example 14 and8-cyclohexyl-2,8-diazaspiro[4.5]decane (500 mg), the obtained crudeproduct was purified by silica gel chromatography (ethylacetate:10%-saturated aqueous ammonia-methanol=1:0→7:3) to obtain thetitle compound (806 mg) having the following physical properties.

Description: amorphous;

TLC: Rf 0.50 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 0.97-1.35 (m, 5H), 1.51-1.67 (m, 6H), 1.67-1.90 (m, 7H),2.14-2.30 (m, 1H), 2.34 (s, 2H), 2.39-2.61 (m, 4H), 3.55 (s, 2H), 4.41(s, 2H), 4.51 (s, 2H), 5.21 (s, 2H), 6.96 (s, 2H), 7.09-7.19 (m, 2H),7.20-7.26 (m, 2H), 7.28-7.48 (m, 5H), 9.63-10.14 (m, 1H).

Example 16N,N-bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)-4-({[trans-4-(dipropylaminoamino)cyclohexyl]amino}methyl)benzamide

The same operation as in Example 2 was performed, except for using thecompound (1.5 g) obtained in Example 4 andtrans-N,N-dipropylcyclohexane-1,4-diamine (682 mg), and then theobtained crude product was purified by silica gel chromatography (ethylacetate:10%-saturated aqueous ammonia-methanol=1:0→8:2) to obtain thetitle compound (1.78 g) having the following physical properties.

Description: amorphous;

TLC: Rf 0.41 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.79 (t, J=7.5 Hz, 6H), 0.89-1.05 (m, 2H), 1.06-1.21(m, 2H), 1.21-1.38 (m, 4H), 1.55-1.68 (m, 2H), 1.82-1.95 (m, 2H),2.14-2.41 (m, 6H), 2.56 (s, 6H), 2.90 (s, 6H), 3.68 (s, 2H), 4.82 (s,2H), 4.96 (s, 2H), 7.05 (d, J=1.5 Hz, 1H), 7.12 (d, J=1.5 Hz, 1H), 7.25(d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.51-7.61 (m, 2H).

Example 17 Methyl(4-{[bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)amino]carbonyl}benzyl)[trans-4-(dipropylaminoamino)cyclohexyl]carbamate

The same operation as in Example 13 was performed, except for using thecompound (200 mg) obtained in Example 16 and methyl chloroformate (54mg), and then the obtained crude product was purified by silica gelchromatography (ethyl acetate:10%-saturated aqueousammonia-methanol=1:0→85:15) to obtain the title compound (210 mg) havingthe following physical properties.

TLC: Rf 0.74 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 7.50 (d, J=8.1 Hz, 2H), 7.25 (m, 2H), 7.20 (m, 2H), 7.08(m, 1H), 6.98 (m, 1H), 5.03 (m, 4H), 4.39 (s, 2H), 3.80 (m, 1H), 3.68(m, 4H), 3.01 (s, 6H), 2.66 (m, 6H), 2.33 (m, 5H), 1.73 (m, 5H), 1.36(m, 6H), 0.83 (t, J=7.5 Hz, 6H).

Example 18 Methyl(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]carbamate

The same operation as in Example 5 was performed, except for using thecompound (205 mg) obtained in Example 18, and then the obtained crudeproduct was purified by silica gel chromatography(dichrolomethane:methanol:28% aqueous ammonia=10:1:0→80:10:1) to obtainthe title compound (58 mg) having the following physical properties.

Description: amorphous;

TLC: Rf 0.33 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.79 (t, J=7.50 Hz, 6H), 1.07-1.80 (m, 12H), 2.11-2.42(m, 5H), 3.44-3.69 (m, 3H), 3.69-3.91 (m, 1H), 4.38 (s, 2H), 4.46-4.70(m, 4H), 6.67-7.09 (m, 4H), 7.19 (d, J=8.10 Hz, 2H), 7.42 (d, J=8.10 Hz,2H), 11.78-12.69 (m, 2H).

Example 18(1) to Example 18(3)

The same operation as in Example 17→Example 18 was performed, except forusing a corresponding chloride in place of methyl chloroformate inExample 17, to obtain the following compound.

Example 18(1) Ethyl(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]carbamate

Description: amorphous;

TLC: Rf 0.46 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.80 (t, J=7.2 Hz, 6H), 0.94-1.81 (m, 15H), 2.12-2.47(m, 5H), 3.61-3.89 (m, 1H), 3.90-4.16 (m, 2H), 4.37 (s, 2H), 4.46-4.72(m, 4H), 6.76-7.11 (m, 4H), 7.19 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz,2H), 11.91-12.59 (m, 2H).

Example 18(2) Phenyl(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]carbamate

Description: amorphous;

TLC: Rf 0.49 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.81 (t, J=7.2 Hz, 6H), 1.11-1.97 (m, 12H), 2.15-2.67(m, 5H), 3.75-4.09 (m, 1H), 4.30-4.80 (m, 6H), 6.75-7.07 (m, 5H),7.09-7.25 (m, 2H), 7.26-7.44 (m, 4H), 7.44-7.62 (m, 2H), 11.91-12.63 (m,2H).

Example 18(3) Benzyl(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]carbamate

Description: amorphous;

TLC: Rf 0.32 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.80 (t, J=7.2 Hz, 6H), 1.14-1.84 (m, 12H), 2.12-2.46(m, 5H), 3.72-3.99 (m, 1H), 4.42 (s, 2H), 4.47-4.68 (m, 4H), 4.95-5.21(m, 2H), 6.84-7.04 (m, 4H), 7.05-7.14 (m, 1H), 7.14-7.27 (m, 4H),7.27-7.40 (m, 2H), 7.43 (d, J=8.4 Hz, 2H), 11.76-12.78 (m, 2H).

Example 192,2′-[{[(4-formylphenyl)sulfonyl]imino}bis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

To a dichloromethane (5 mL) solution of the compound (500 mg) obtainedin Example 3 and triethylamine (0.27 mL), 4-formylbenzenesulfonylchloride (340 mg) was added at 0° C. The reaction solution was stirredat 0° C. for 16 hours. To the reaction solution, water (30 mL) wasadded, followed by extraction of the aqueous layer twice withdichloromethane (50 mL). The combined organic layer was washed withsaturated brine and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous sodium sulfate by filtration, the filtrate wasconcentrated. The residue was washed with ethyl acetate and thenpurified to obtain the title compound (606 mg) having the followingphysical properties.

TLC: Rf 0.67 (ethyl acetate);

NMR (DMSO-d₆): δ 2.83 (s, 12H), 5.01 (s, 4H), 6.86 (d, J=1.8 Hz, 2H),7.48 (d, J=1.8 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 8.00 (d, J=8.1 Hz, 2H),10.06 (s, 1H).

Example 20 4-formyl-N,N-bis(1H-imidazol-2-ylmethyl)benzenesulfonamide

The same operation as in Example 5 was performed, except for using thecompound (600 mg) obtained in Example 19, to obtain the title compound(373 mg) having the following physical properties.

TLC: Rf 0.49 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CD₃OD): δ 4.59 (s, 4H), 6.91 (s, 4H), 7.72 (d, J=8.0 Hz, 2H), 7.92(d, J=8.0 Hz, 2H), 10.02 (s, 1H).

Example 214-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzenesulfonamide

With the compound produced in Example 20 and8-cyclohexyl-2,8-diazaspiro[4.5]decane dihydrochloride, the sameoperation as in Example 2 was performed to obtain the title compoundhaving the following physical properties.

Description: amorphous;

TLC: Rf 0.49 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.10-1.30 (m, 6H), 1.60-1.68 (m, 8H), 1.79-1.92 (m, 4H),2.29 (m, 1H), 2.50-2.62 (m, 6H), 3.62 (s, 2H), 4.52 (s, 4H), 6.91 (s,4H), 7.41 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H).

Example 21(1) to Example 21(21)

Except for using the corresponding aldehyde in Example 21 in place ofthe compound produced in Example 20 and using the corresponding aminesalt or amine in place of 8-cyclohexyl-2,8-diazaspiro[4.5]decanedihydrochloride, the same operation as in Example 21 was performed toobtain the following compound.

Example 21(1)4-({[trans-4-(dipropylamino)cyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.33 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.80 (t, J=6.90 Hz, 6H), 0.90-1.07 (m, 2H), 1.07-1.24(m, 2H), 1.23-1.43 (m, 4H), 1.56-1.73 (m, 2H), 1.82-1.98 (m, 2H),2.14-2.45 (m, 6H), 3.73 (s, 2H), 4.49 (s, 4H), 6.75-7.09 (m, 4H), 7.41(d, J=8.10 Hz, 2H), 7.54 (d, J=8.10 Hz, 2H), 11.86-12.93 (m, 2H).

Example 21(2)N,N-bis(1H-imidazol-2-ylmethyl)-4-({[trans-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)cyclohexyl]amino}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.68 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (DMSO-d₆): δ 0.90-1.10 (m, 2H), 1.10-1.30 (m, 2H), 1.62-1.78 (m,2H), 1.82-1.97 (m, 2H), 2.00-2.16 (m, 4H), 2.16-2.30 (m, 1H), 2.34-2.46(m, 1H), 2.51-2.60 (m, 4H), 3.73 (s, 2H), 4.48 (s, 4H), 5.71 (t, J=3.00Hz, 2H), 6.78-7.04 (m, 4H), 7.41 (d, J=8.40 Hz, 2H), 7.54 (d, J=8.40 Hz,2H), 11.60-13.13 (m, 2H).

Example 21(3)N,N-bis(1H-imidazol-2-ylmethyl)-4-({[trans-4-(1-piperidinyl)cyclohexyl]amino}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.66 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (DMSO-d₆): δ 0.89-1.09 (m, 2H), 1.09-1.27 (m, 2H), 1.28-1.38 (m,2H), 1.38-1.52 (m, 4H), 1.63-1.78 (m, 2H), 1.83-1.99 (m, 2H), 2.10-2.29(m, 2H), 2.34-2.46 (m, 4H), 3.73 (s, 2H), 4.48 (s, 4H), 6.66-7.19 (m,4H), 7.41 (d, J=8.40 Hz, 2H), 7.54 (d, J=8.40 Hz, 2H), 12.10-12.77 (m,2H).

Example 21(4)4-({[trans-4-(1-azepanyl)cyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.58 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (DMSO-d₆): δ 0.89-1.08 (m, 2H), 1.08-1.29 (m, 2H), 1.43-1.56 (m,8H), 1.61-1.76 (m, 2H), 1.80-1.98 (m, 2H), 2.13-2.28 (m, 1H), 2.29-2.44(m, 1H), 2.52-2.62 (m, 4H), 3.73 (s, 2H), 4.48 (s, 4H), 6.69-7.13 (m,4H), 7.41 (d, J=8.20 Hz, 2H), 7.54 (d, J=8.10 Hz, 2H), 12.15-12.71 (m,2H).

Example 21(5)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.47 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.37-1.65 (m, 6H), 2.12 (s, 3H), 2.17-2.31 (m, 4H),2.34 (s, 2H), 2.52-2.61 (m, 2H), 3.43 (s, 2H), 3.62 (s, 2H), 4.51 (s,4H), 6.67-7.10 (m, 5H), 7.25 (d, J=5.10 Hz, 1H), 7.33 (d, J=8.10 Hz,2H), 7.51 (d, J=8.10 Hz, 2H), 12.03-12.82 (m, 2H).

Example 21(6)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzenesulfonamide

Description: amorphous;

TLC: Rf 0.33 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.19-1.33 (m, 2H), 1.33-1.62 (m, 6H), 2.03-2.21 (m,4H), 2.21-2.42 (m, 4H), 3.40 (s, 2H), 3.60 (s, 2H), 4.51 (s, 4H),6.62-7.16 (m, 6H), 7.23-7.34 (m, J=8.10 Hz, 2H), 7.38 (dd, J=5.10, 1.50Hz, 1H), 7.49 (d, J=8.10 Hz, 2H), 12.04-12.65 (m, 2H).

Example 21(7)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.31 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.17-1.32 (m, 2H), 1.32-1.59 (m, 6H), 2.02-2.20 (m,7H), 2.21-2.40 (m, 4H), 3.40 (s, 2H), 3.48 (s, 2H), 4.50 (s, 4H),6.70-7.06 (m, 5H), 7.26 (d, J=4.80 Hz, 1H), 7.30 (d, J=8.70 Hz, 2H),7.49 (d, J=8.70 Hz, 2H), 12.01-12.73 (m, 2H).

Example 21(8)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzenesulfonamide

Description: amorphous;

TLC: Rf 0.36 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.13-1.34 (m, 2H), 1.36-1.63 (m, 6H), 1.92-2.12 (m,2H), 2.17-2.39 (m, 6H), 3.42 (s, 2H), 3.59 (s, 2H), 4.52 (s, 4H),6.71-6.85 (m, 2H), 6.85-6.94 (m, 2H), 6.94-7.11 (m, 2H), 7.28-7.40 (m,3H), 7.53 (d, J=7.80 Hz, 2H), 12.14-12.58 (m, 2H).

Example 21(9)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.36 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.19-1.35 (m, 2H), 1.36-1.60 (m, 6H), 2.00-2.07 (m,2H), 2.09 (s, 3H), 2.19-2.40 (m, 6H), 3.42 (s, 2H), 3.50 (s, 2H), 4.52(s, 4H), 6.78 (d, J=5.10 Hz, 1H), 6.82-6.99 (m, 4H), 7.25 (d, J=5.10 Hz,1H), 7.34 (d, J=8.40 Hz, 2H), 7.52 (d, J=8.40 Hz, 2H), 11.80-13.16 (m,2H).

Example 21(10)N,N-bis(1H-imidazol-2-ylmethyl)-4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.35 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.39-1.59 (m, 2H), 1.70-1.90 (m, 2H), 2.13 (s, 3H),2.17-2.44 (m, 6H), 3.16 (s, 2H), 3.45 (s, 2H), 3.51 (s, 2H), 3.56-3.65(m, 2H), 4.51 (s, 4H), 6.66-7.13 (m, 5H), 7.29 (d, J=5.10 Hz, 1H), 7.33(d, J=8.40 Hz, 2H), 7.50 (d, J=8.40 Hz, 2H), 12.08-12.65 (m, 2H).

Example 21(11)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzenesulfonamide

Description: amorphous;

TLC: Rf 0.65 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.45-1.55 (m, 8H), 2.31-2.37 (m, 4H), 2.40-2.47 (m, 4H),3.50 (s, 2H), 3.73 (s, 2H), 4.44 (s, 4H), 6.89-6.91 (m, 1H), 6.94 (dd,J=5.1, 3.6 Hz, 1H), 7.00 (s, 4H), 7.22 (dd, J=5.1, 0.9 Hz, 1H), 7.39 (d,J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H).

Example 21(12)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.65 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.45-1.55 (m, 8H), 2.19 (s, 3H), 2.31-2.38 (m, 4H),2.40-2.48 (m, 4H), 3.50 (s, 2H), 3.63 (s, 2H), 4.44 (s, 4H), 6.78 (d,J=5.1 Hz, 1H), 7.00 (s, 4H), 7.12 (d, J=5.1 Hz, 1H), 7.40 (d, J=8.4 Hz,2H), 7.69 (d, J=8.4 Hz, 2H).

Example 21(13) Ethyl{(4-{[bis(1H-imidazol-2-ylmethyl)amino]sulfonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]amino}acetate

Description: amorphous;

TLC: Rf 0.26 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.82 (t, J=7.50 Hz, 6H), 1.16 (t, J=7.20 Hz, 3H),1.20-1.51 (m, 8H), 1.66-1.91 (m, 4H), 2.22-2.65 (m, 6H), 3.29 (s, 2H),3.76 (s, 2H), 4.04 (q, J=7.20 Hz, 2H), 4.51 (s, 4H), 6.75-7.01 (m, 4H),7.42 (d, J=8.70 Hz, 2H), 7.51 (d, J=8.70 Hz, 2H), 11.86-12.89 (m, 2H).

Example 21(14){(4-{[bis(1H-imidazol-2-ylmethyl)amino]sulfonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]amino}aceticacid dihydrochloride

Description: amorphous;

TLC: Rf 0.16 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (DMSO-d₆): δ 0.90 (t, J=7.20 Hz, 6H), 1.54-1.86 (m, 8H), 2.10-2.34(m, 4H), 2.79-3.16 (m, 4H), 3.17-3.52 (m, 2H), 4.01 (s, 2H), 4.51 (s,2H), 4.93 (s, 4H), 7.64 (s, 4H), 7.88-8.08 (m, 4H), 10.33-10.61 (m, 2H).

Example 21(15) Ethyl{(4-{[bis(1H-imidazol-2-ylmethyl)amino]sulfonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]amino}acetate

Description: amorphous;

TLC: Rf 0.26 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.82 (t, J=7.50 Hz, 6H), 1.16 (t, J=7.20 Hz, 3H),1.20-1.51 (m, 8H), 1.66-1.91 (m, 4H), 2.22-2.65 (m, 6H), 3.29 (s, 2H),3.76 (s, 2H), 4.04 (q, J=7.20 Hz, 2H), 4.51 (s, 4H), 6.75-7.01 (m, 4H),7.42 (d, J=8.70 Hz, 2H), 7.51 (d, J=8.70 Hz, 2H), 11.86-12.89 (m, 2H).

Example 21(16){(4-{[bis(1H-imidazol-2-ylmethyl)amino]sulfonyl}benzyl)[trans-4-(dipropylamino)cyclohexyl]amino}aceticacid dihydrochloride

Description: amorphous;

TLC: Rf 0.16 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (DMSO-d₆): δ 0.90 (t, J=7.20 Hz, 6H), 1.54-1.86 (m, 8H), 2.10-2.34(m, 4H), 2.79-3.16 (m, 4H), 3.17-3.52 (m, 2H), 4.01 (s, 2H), 4.51 (s,2H), 4.93 (s, 4H), 7.64 (s, 4H), 7.88-8.08 (m, 4H), 10.33-10.61 (m, 2H).

Example 21(17)N,N-bis(1H-imidazol-2-ylmethyl)-4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[4.4]non-2-yl}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.62-1.98 (m, 4H), 2.18 (s, 3H), 2.34-2.76 (m, 8H), 3.61(s, 2H), 3.71 (s, 2H), 4.43 (s, 4H), 6.78 (d, J=5.1 Hz, 1H), 7.02 (s,4H), 7.11 (d, J=5.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz,2H), 10.58-11.24 (m, 2H).

Example 21(18)N,N-bis(1H-imidazol-2-ylmethyl)-4-({[(3S)-1-(1-propylbutyl)-3-piperidinyl]amino}methyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.28 (ethyl acetate:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 0.86-0.94 (m, 6H), 1.12-1.59 (m, 10H), 1.61-1.74 (m, 1H),1.85 (s, 1H), 2.13-2.25 (m, 1H), 2.27-2.44 (m, 2H), 2.52-2.66 (m, 2H),2.82 (dd, J=10.8, 3.3 Hz, 1H), 3.82 (s, 2H), 4.51 (s, 4H), 6.92 (s, 4H),7.44 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H).

Example 21(19)N,N-bis(1H-imidazol-2-ylmethyl)-4-[({(3S)-1-[(3-methyl-2-thienyl)methyl]-3-piperidinyl}amino)methyl]benzenesulfonamide

Description: amorphous;

TLC: Rf 0.17 (ethyl acetate:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 1.14-1.30 (m, 1H), 1.47-1.63 (m, 1H), 1.65-1.79 (m, 1H),1.82-2.07 (m, 2H), 2.08-2.22 (m, 4H), 2.55-2.67 (m, 1H), 2.74 (d, J=11.1Hz, 1H), 2.91 (d, J=9.9 Hz, 1H), 3.59-3.67 (m, 2H), 3.77 (s, 2H), 4.50(s, 4H), 6.80 (d, J=5.1 Hz, 1H), 6.92 (s, 4H), 7.20 (d, J=5.1 Hz, 1H),7.39 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H).

Example 21(20)4-{[(3S)-3-(dipropylamino)-1-piperidinyl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzenesulfonamide

Description: amorphous;

TLC: Rf 0.30 (ethyl acetate:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 0.86 (t, J=7.5 Hz, 6H), 1.17-1.64 (m, 6H), 1.68-1.97 (m,4H), 2.38-2.49 (m, 4H), 2.68-2.81 (m, 2H), 2.92 (dd, J=10.5, 1.5 Hz,1H), 3.52-3.60 (m, 2H), 4.52 (s, 4H), 6.91 (s, 4H), 7.42 (d, J=8.7 Hz,2H), 7.54-7.61 (m, 2H).

Example 21(21)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzenesulfonamide

Description: amorphous;

TLC: Rf 0.33 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.66-1.95 (m, 4H), 2.34-2.74 (m, 8H), 3.61 (s, 2H), 3.80(s, 2H), 4.43 (s, 4H), 6.87-6.91 (m, 1H), 6.93 (dd, J=5.1, 3.6 Hz, 1H),7.02 (s, 4H), 7.21 (dd, J=5.1, 1.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.70(d, J=8.4 Hz, 2H), 10.59-11.36 (m, 2H).

Example 22 Tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate

To anhydrous tetrahydrofuran (30 mL) solution oftrans-4-[(tert-butoxycarbonyl)amino]cyclohexanecalboxylic acid (2.17 g),1N-boran-tetrahydrofuran complex/tetrahydrofuran solution (17.8 mL) wasslowly added at 0° C. The reaction solution was stirred at 0° C. for 2hours. To the reaction solution, an aqueous saturated sodium hydrogencarbonate solution (100 mL) was added, and then aqueous layer wasextracted twice with 100 mL of ethyl acetate. The combined organic layerwas washed with saturated brine and then dried over anhydrous magnesiumsulfate. After removing the anhydrous sodium sulfate by filtration, thefiltrate was concentrated. Without purifying the residue, the titlecompound (1.6 g) having the following physical properties was obtained.

TLC: Rf 0.60 (ethyl acetate);

NMR (CDCl₃): δ 0.97-1.16 (m, 4H), 1.44 (s, 9H), 1.80-1.84 (m, 2H),2.03-2.06 (m, 2H), 3.31 (m, 1H), 3.45 (d, J=6.6 Hz, 2H), 4.37 (m, 1H).

Example 23 Tert-butyl (trans-4-formylcyclohexyl)carbamate

To a dichloromethane (30 mL) solution of the compound (1.6 g) obtainedin Example 22, a Dess-Martin reagent (3.97 g) was added at 0° C. Thereaction solution was stirred at room temperature for 16 hours. To thereaction solution, an aqueous saturated sodium hydrogen carbonatesolution (50 mL) was added, and then aqueous layer was extracted withdichloromethane. The combined organic layer was washed with saturatedbrine and then dried over anhydrous magnesium sulfate. After removingthe anhydrous sodium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(n-hexane:ethyl acetate=1:0→8:2) to obtain the title compound (1.60 g)having the following physical properties.

TLC: Rf 0.80 (ethyl acetate);

NMR (DMSO-d₆): δ 1.09-1.24 (m, 4H), 1.45 (s, 9H), 2.00-2.20 (m, 4H),3.39 (m, 1H), 4.40 (m, 1H), 9.60 (d, J=1.2 Hz, 1H).

Example 24 Tert-butyl{trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}carbamate

The same operation as in Example 2 was performed, except for using thecompound (402 mg) obtained in Example 23 and8-cyclohexyl-2,8-diazaspiro[4.5]decane (500 mg), to obtain the titlecompound (806 mg) having the following physical properties.

TLC: Rf 0.55 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 0.91-1.86 (m, 24H), 1.45 (s, 9H), 1.99-2.05 (m, 2H), 2.18(d, J=7.2 Hz, 2H), 2.28 (s, 2H), 2.46-2.51 (m, 5H), 3.35 (m, 1H), 4.35(m, 1H).

Example 25Trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexaneaminetrihydrochloride

To a methanol (3 mL) solution of the compound (806 mg) obtained inExample 24, a 4N-hydrogen chloride/1,4-dioxane solution (6 mL) wasadded. The reaction solution was stirred at room temperature for 2hours. The reaction solution was concentrated under reduced pressure.The title compound (749 mg) having the following physical propertieswere obtained without purifying the residue.

TLC: Rf 0.17 (dichrolomethane:methanol:28% aqueous ammonia=50:10:1);

NMR (CD₃OD): δ 1.19-2.24 (m, 24H), 3.00-4.00 (m, 12H).

Example 26Trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

With the compound produced in Example 25 and1H-imidazole-2-carbaldehyde, the same operation as in Example 2 wasperformed to obtain the title compound having the following physicalproperties.

Description: amorphous;

TLC: Rf 0.55 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 0.79-0.90 (m, 2H), 1.10-1.31 (m, 8H), 1.54-1.65 (m, 7H),1.81-1.90 (m, 8H), 2.15 (d, J=6.9 Hz, 2H), 2.27 (s, 2H), 2.30 (m, 1H),2.46-2.56 (m, 7H), 3.77 (br-s, 4H), 6.98 (br-s, 4H).

Example 26(1) to Example 26(16)

The same operation as in Example 26 was performed, except for using thecorresponding amine in place of the compound obtained in Example 25 inExample 26, to obtain the following compound.

Example 26(1)Cis-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.70 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 1.00-1.94 (m, 25H), 2.18-2.63 (m, 12H), 3.71 (s, 4H),7.02 (s, 4H).

Example 26(2)Trans-4-[(8-cyclopentyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.69 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.75-0.98 (m, 4H), 1.14-1.96 (m, 19H), 2.15 (d, J=7.2 Hz,2H), 2.27 (s, 2H), 2.29-2.59 (m, 8H), 3.77 (s, 4H), 6.98 (s, 4H).

Example 26(3)Trans-N,N-bis(1H-imidazol-2-ylmethyl)-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexanamine

Description: amorphous;

TLC: Rf 0.69 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.75-1.96 (m, 16H), 0.88 (d, J=6.6 Hz, 6H), 2.04 (d,J=7.2 Hz, 2H), 2.16 (d, J=6.9 Hz, 2H), 2.20-2.58 (m, 9H), 3.78 (s, 4H),6.99 (s, 4H).

Example 26(4)Trans-N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.69 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.77-1.98 (m, 15H), 2.05-2.63 (m, 14H), 3.58 (s, 2H),3.68-3.79 (m, 4H), 6.77 (d, J=5.1 Hz, 1H), 6.98-7.02 (m, 4H), 7.10 (d,J=5.1 Hz, 1H).

Example 26(5)4-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.60 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 1.00-2.02 (m, 24H), 2.04-2.68 (m, 9H), 2.41 (s, 2H), 3.68(s, 4H), 7.02 (s, 4H).

Example 26(6)1-{trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.60 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.76-1.94 (m, 26H), 2.14-2.38 (m, 2H), 2.19 (d, J=6.9 Hz,2H), 2.29 (s, 2H), 2.32 (d, J=6.9 Hz, 2H), 2.42-2.56 (m, 5H), 3.58 (s,4H), 7.05 (s, 4H).

Example 26(7)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)-N-(2-pyridinylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.85 (m, 1H), 1.00-1.98 (m, 24H), 2.12-2.38 (m, 5H),2.42-2.60 (m, 7H), 3.80-3.94 (m, 4H), 6.97-7.02 (m, 2H), 7.18-7.32 (m,2H), 7.65 (m, 1H), 8.62 (m, 1H).

Example 26(8)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)-N-[(6-methyl-2-pyridinyl)methyl]cyclohexanamine

Description: amorphous;

TLC: Rf 0.32 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.85 (m, 1H), 1.00-2.00 (m, 24H), 2.10-2.34 (m, 5H),2.40-2.57 (m, 7H), 2.62 (s, 3H), 3.78-3.94 (m, 4H), 6.97-7.11 (m, 4H),7.55 (m, 1H), 12.55 (m, 1H).

Example 26(9)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)-N-[(3-methyl-2-pyridinyl)methyl]cyclohexanamine

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.88 (m, 1H), 1.00-1.97 (m, 24H), 2.12-2.34 (m, 5H),2.38-2.60 (m, 10H), 3.70-3.90, (m, 4H), 6.98-7.05 (m, 2H), 7.16 (m, 1H),7.49 (m, 1H), 8.45 (m, 1H), 12.28 (m, 1H).

Example 26(10)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)-N-(1,3-oxazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.28 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.88 (m, 1H), 1.00-1.97 (m, 24H), 2.12-2.35 (m, 5H),2.42-2.61 (m, 7H), 3.87-3.92, (m, 4H), 6.98-7.02 (m, 2H), 7.10 (m, 1H),7.63 (m, 1H), 10.89 (m, 1H).

Example 26(11)Trans-4-[(9-cyclohexyl-2,9-diazaspiro[5.5]undec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.61 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.65-2.10 (m, 29H), 2.16-2.33 (m, 4H), 2.39-2.59 (m, 6H),3.80 (s, 4H), 7.01 (s, 4H).

Example 26(12)Trans-4-[(7-cyclohexyl-2,7-diazaspiro[4.4]non-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.43 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.72-2.07 (m, 23H), 2.18 (d, J=7.2 Hz, 2H), 2.27-2.79 (m,10H), 3.79 (s, 4H), 7.01 (s, 4H).

Example 26(13)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)-N-(1,3-thiazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.28 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.85 (m, 1H), 1.00-1.96 (m, 24H), 2.10-2.34 (m, 5H),2.38-2.60 (m, 7H), 3.85-3.93, (m, 2H), 4.00-4.06 (m, 2H), 6.98-7.02 (m,2H), 7.28 (m, 1H), 7.73 (m, 1H), 10.07-10.21 (m, 1H).

Example 26(14)Trans-4-[(7-cyclohexyl-2,7-diazaspiro[3.5]non-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.60 (dichrolomethane:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.74-1.95 (m, 23H), 2.16-2.29 (m, 3H), 2.36-2.55 (m, 5H),2.93 (s, 4H), 3.76 (s, 4H), 7.00 (s, 4H).

Example 26(15)Trans-4-[(9-cyclohexyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.50 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.72-1.96 (m, 27H), 2.00-2.11 (m, 2H), 2.16-2.33 (m, 5H),2.40-2.60 (m, 5H), 3.78 (s, 4H), 7.01 (s, 4H).

Example 26(16)Trans-4-[(9-cyclohexyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.58 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.64-2.03 (m, 25H), 2.11 (s, 2H), 2.22-2.35 (m, 3H),2.43-2.65 (m, 5H), 3.68 (t, J=4.8 Hz, 2H), 3.79 (s, 4H), 7.01 (s, 4H).

Example 272,2′-[{[4-(diethoxymethyl)benzyl]imino}bis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

With 4-(diethoxymethyl)benzaldehyde (250 mg) and the compound producedin Example 3 (470 mg), the same operation as in Example 2 was performed.The obtained crude product was purified by silica gel chromatography(ethyl acetate:10%-saturated aqueous ammonia-methanol=1:0→10:1) toobtain the title compound (580 mg) having the following physicalproperties.

TLC: Rf 0.56 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 7.79 (m, 1H), 7.54 (m, 1H), 7.35 (m, 2H), 7.23 (m, 2H),6.99 (m, 2H), 5.45 (s, 1H), 4.18 (m, 4H), 4.11 (s, 2H), 3.56 (m, 4H),2.80 (s, 12H), 1.23 (m, 6H).

Example 28 4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzaldehyde

Except for using the compound (575 mg) produced in Example 27, the sameoperation as in Example 5 was performed to obtain the title compound(290 mg) having the following physical properties.

Description: amorphous;

TLC: Rf 0.53 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (CDCl₃): δ 9.92 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz,2H), 6.99 (s, 4H), 3.70 (s, 4H), 3.62 (s, 2H).

Example 291-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[8-(2-thienylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzyl)methanamine

With the compound produced in Example 28 (80 mg) and8-(2-thienyl)-2,8-diazaspiro[4.5]decane (160 mg), the same operation asin Example 2 was performed. The obtained crude product was purified bysilica gel chromatography (ethyl acetate:10%-saturated aqueousammonia-methanol=1:0→7:3) to obtain the title compound (122 mg) havingthe following physical properties.

Description: amorphous;

TLC: Rf 0.29 (28% aqueous ammonia:methanol=2:98);

NMR (CDCl₃): δ 1.55-1.67 (m, 6H), 2.32-2.46 (m, 6H), 2.54-2.65 (m, 2H),3.55-3.65 (m, 8H), 3.67 (s, 2H), 6.86-6.97 (m, 2H), 7.03 (s, 4H),7.18-7.31 (m, 5H).

Example 29(1) to Example 29(61)

The same operation as in Example 27→Example 28→Example 29 was performed,except for using a corresponding aldehyde and a corresponding amine inplace of 4-(diethoxymethyl)benzaldehyde and the compound obtained inExample 3 in Example 27, and a corresponding amine in place of8-(2-thienyl)-2,8-diazaspiro[4.5]decane in Example 29, to obtain thetitle compound having the following physical properties.

Example 29(1)N-(1H-benzimidazol-2-ylmethyl)-N-[4-(2,8-diazaspiro[4.5]dec-2-ylmethyl)benzyl]-5,6,7,8-tetrahydroquinolin-8-amine

Description: amorphous;

TLC: Rf 0.24 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.29-1.43 (m, 4H), 1.49 (t, J=7.2 Hz, 2H), 1.53-1.68(m, 1H), 1.82-2.05 (m, 2H), 2.08-2.21 (m, 1H), 2.23 (s, 2H), 2.39 (t,J=7.2 Hz, 2H), 2.53-2.70 (m, 5H), 2.70-2.87 (m, 1H), 3.43 (s, 2H),3.64-3.78 (m, 1H), 3.83-4.01 (m, 3H), 4.01-4.11 (m, 1H), 7.03-7.13 (m,2H), 7.15 (d, J=7.8 Hz, 2H), 7.21 (dd, J=7.8, 4.8 Hz, 1H), 7.35 (d,J=7.8 Hz, 2H), 7.44-7.57 (m, 3H), 8.59 (dd, J=4.8, 1.2 Hz, 1H),12.20-12.92 (m, 1H).

Example 29(2)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.23 (28% aqueous ammonia:methanol=2:98);

NMR (CDCl₃): δ 1.54-1.67 (m, 6H), 2.17 (s, 3H), 2.32-2.47 (m, 6H),2.54-2.67 (m, 2H), 3.54-3.68 (m, 10H), 6.73-6.80 (m, 1H), 7.00-7.08 (m,4H), 7.08-7.13 (m, 1H), 7.20-7.32 (m, 4H).

Example 29(3)4-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-N,N-bis(1H-imidazol-2-ylmethyl)butan-1-amine

TLC: Rf 0.91 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.14-1.33 (m, 5H), 1.36-1.52 (m, 4H), 1.55-1.68 (m, 6H),1.79-2.03 (m, 5H), 2.23-2.46 (m, 8H), 2.49-2.63 (m, 5H), 3.68 (s, 4H),6.99 (s, 4H).

Example 29(4)N,N-bis(1H-imidazol-2-ylmethyl)-4-{8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}butan-1-amine

TLC: Rf 0.91 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.34-1.52 (m, 5H), 1.52-1.72 (m, 5H), 2.19 (s, 3H),2.25-2.61 (m, 12H), 3.62 (s, 2H), 3.68 (s, 4H), 6.78 (d, J=5.1 Hz, 1H),6.98 (s, 4H), 7.18 (d, J=5.1 Hz, 1H).

Example 29(5)N-(1H-benzimidazol-2-ylmethyl)-N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-5,6,7,8-tetrahydroquinolin-8-amine

Description: amorphous;

TLC: Rf 0.43 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.96-1.29 (m, 5H), 1.33-1.55 (m, 8H), 1.59-1.74 (m,4H), 1.83-2.03 (m, 2H), 2.06-2.25 (m, 4H), 2.26-2.46 (m, 5H), 2.56-2.89(m, 3H), 3.42 (s, 2H), 3.70 (d, J=13.50 Hz, 1H), 3.82-4.13 (m, 4H),7.00-7.16 (m, 4H), 7.20 (dd, J=7.80, 4.80 Hz, 1H), 7.33 (d, J=7.80 Hz,2H), 7.42-7.56 (m, 3H), 8.50-8.65 (m, 1H), 12.48 (s, 1H).

Example 29(6)N,N-bis(1H-imidazol-2-ylmethyl)-3-{8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}propan-1-amine

Description: amorphous;

TLC: Rf 0.70 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.48-1.69 (m, 8H), 2.19 (s, 3H), 2.26-2.61 (m, 12H), 3.62(s, 2H), 3.69 (s, 4H), 6.79 (d, J=5.1 Hz, 1H), 6.98 (s, 4H), 7.19 (d,J=5.1 Hz, 1H).

Example 29(7)N,N-bis(1H-imidazol-2-ylmethyl)-5-{8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}-1-pentanamine

Description: amorphous;

TLC: Rf 0.70 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.16-1.30 (m, 2H), 1.33-1.51 (m, 4H), 1.55-1.69 (m, 6H),2.19 (s, 3H), 2.29-2.51 (m, 10H), 2.53-2.66 (m, 2H), 3.62 (s, 2H), 3.68(s, 4H), 6.78 (d, J=5.1 Hz, 1H), 6.97 (s, 4H), 7.18 (d, J=5.1 Hz, 1H).

Example 29(8)N,N-bis(1H-imidazol-2-ylmethyl)-6-{8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}hexane-1-amine

TLC: Rf 0.75 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.11-1.32 (m, 4H), 1.34-1.50 (m, 4H), 1.54-1.72 (m, 6H),2.19 (s, 3H), 2.26-2.53 (m, 10H), 2.53-2.63 (m, 2H), 3.62 (s, 2H), 3.68(s, 4H), 6.78 (d, J=5.1 Hz, 1H), 6.97 (s, 4H), 7.18 (d, J=5.1 Hz, 1H).

Example 29(9)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-(2-pyridinylmethyl)methanamine

TLC: Rf 0.80 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.04-1.31 (m, 6H), 1.55-1.67 (m, 6H), 1.74-1.92 (m, 4H),2.21-2.33 (m, 1H), 2.38 (s, 2H), 2.46-2.63 (m, 6H), 3.55 (s, 2H), 3.57(s, 2H), 3.69 (s, 2H), 3.70 (s, 2H), 6.96 (s, 2H), 7.16-7.39 (m, 5H),7.54-7.66 (m, 1H), 7.78 (dt, J=7.8, 1.8 Hz, 1H), 8.41-8.50 (m, 1H).

Example 29(10)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-(3-pyridinylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.78 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.11-1.33 (m, 6H), 1.54-1.68 (m, 6H), 1.74-1.92 (m, 4H),2.21-2.33 (m, 1H), 2.39 (s, 2H), 2.48-2.63 (m, 6H), 3.57 (s, 2H), 3.58(s, 2H), 3.59 (s, 2H), 3.67 (s, 2H), 6.93 (s, 2H), 7.28 (d, J=8.1 Hz,2H), 7.31-7.37 (m, 3H), 7.79-7.87 (m, 1H), 8.36 (dd, J=4.8, 1.5 Hz, 1H),8.47 (d, J=1.5 Hz, 1H).

Example 29(11)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-(4-pyridinylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.78 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.01-1.32 (m, 6H), 1.52-1.68 (m, 6H), 1.72-1.91 (m, 4H),2.21-2.32 (m, 1H), 2.38 (s, 2H), 2.46-2.64 (m, 6H), 3.57 (s, 2H), 3.59(s, 4H), 3.68 (s, 2H), 6.94 (s, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.36 (d,J=8.1 Hz, 2H), 7.45 (d, J=6.0 Hz, 2H), 8.40 (d, J=6.0 Hz, 2H).

Example 29(12)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(3-methyl-2-pyridinyl)methyl]methanamine

TLC: Rf 0.63 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.06-1.42 (m, 6H), 1.55-1.69 (m, 6H), 1.74-1.92 (m, 4H),2.20 (s, 3H), 2.23-2.33 (m, 1H), 2.37 (s, 2H), 2.48-2.62 (m, 6H), 3.53(s, 2H), 3.55 (s, 2H), 3.68 (s, 2H), 3.70 (s, 2H), 6.97 (s, 2H),7.11-7.29 (m, 5H), 7.46-7.60 (m, 1H), 8.30 (dd, J=5.1, 1.2 Hz, 1H).

Example 29(13)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-(1H-imidazol-2-ylmethyl)-2-(1-piperidinyl)ethanamine

TLC: Rf 0.85 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.14-1.31 (m, 6H), 1.50-1.70 (m, 12H), 1.77-1.96 (m, 4H),2.21-2.67 (m, 17H), 3.56 (s, 2H), 3.60 (s, 2H), 3.70 (s, 2H), 6.96 (s,2H), 7.19-7.35 (m, 4H).

Example 29(14)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-(1H-imidazol-2-ylmethyl)-2-(4-morpholinyl)ethanamine

TLC: Rf 0.83 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.15-1.32 (m, 6H), 1.53-1.68 (m, 6H), 1.73-1.96 (m, 4H),2.19-2.64 (m, 17H), 3.56 (s, 2H), 3.59-3.65 (m, 6H), 3.72 (s, 2H), 6.96(s, 2H), 7.16-7.39 (m, 4H).

Example 29(15)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-2-(1H-imidazol-1-yl)-N-(1H-imidazol-2-ylmethyl)ethanamine

TLC: Rf 0.74 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.03-1.39 (m, 6H), 1.59-1.74 (m, 6H), 1.79-2.04 (m, 4H),2.42 (s, 2H), 2.48-2.68 (m, 3H), 2.68-2.85 (m, 6H), 3.58 (s, 2H), 3.62(s, 2H), 3.74 (s, 2H), 3.96 (t, J=6.3 Hz, 2H), 6.82-6.89 (m, 1H),6.91-7.06 (m, 3H), 7.10-7.37 (m, 4H), 7.50 (t, J=1.2 Hz, 1H).

Example 29(16)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-2-(1H-imidazol-4-yl)-N-(1H-imidazol-2-ylmethyl)ethanamine

TLC: Rf 0.72 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.08-1.36 (m, 6H), 1.51-1.69 (m, 6H), 1.74-1.99 (m, 4H),2.19-2.43 (m, 3H), 2.49-2.79 (m, 10H), 3.56 (s, 2H), 3.63 (s, 2H), 3.73(s, 2H), 6.68 (s, 1H), 6.95 (s, 2H), 7.18-7.32 (m, 4H), 7.51 (d, J=1.1Hz, 1H).

Example 29(17)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[7-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.73-1.80 (m, 4H), 2.29-2.42 (m, 4H), 3.04 (s, 4H), 3.59(s, 4H), 3.61 (s, 2H), 3.62 (s, 2H), 3.65 (s, 2H), 6.85-6.89 (m, 1H),6.93 (dd, J=5.1, 3.3 Hz, 1H), 7.05 (s, 4H), 7.18-7.23 (m, 3H), 7.29 (d,J=8.1 Hz, 2H).

Example 29(18)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-2-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.39 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.72-1.80 (m, 4H), 2.16 (s, 3H), 2.27-2.43 (m, 4H), 3.04(s, 4H), 3.54 (s, 2H), 3.59 (s, 4H), 3.60 (s, 2H), 3.61-3.63 (m, 2H),6.77 (d, J=4.8 Hz, 1H), 7.05 (s, 4H), 7.11 (d, J=4.8 Hz, 1H), 7.20 (d,J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H).

Example 29(19)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.70-1.78 (m, 4H), 2.24-2.38 (m, 4H), 3.04 (s, 4H), 3.40(s, 2H), 3.60 (s, 4H), 3.62 (s, 2H), 3.78-3.81 (m, 2H), 6.87-6.90 (m,1H), 6.93 (dd, J=5.1, 3.6 Hz, 1H), 7.05 (s, 4H), 7.21 (dd, J=5.1, 1.2Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H).

Example 29(20)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.34 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.70-1.79 (m, 4H), 2.17 (s, 3H), 2.23-2.41 (m, 4H), 3.04(s, 4H), 3.40 (s, 2H), 3.60 (s, 4H), 3.62 (s, 2H), 3.71 (s, 2H), 6.78(d, J=5.1 Hz, 1H), 7.05 (s, 4H), 7.09 (d, J=5.1 Hz, 1H), 7.23 (d, J=8.1Hz, 2H), 7.30 (d, J=8.1 Hz, 2H).

Example 29(21)N-benzyl-1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.59 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 1.13-1.36 (m, 6H), 1.53-1.72 (m, 6H), 1.74-1.99 (m, 4H),2.24-2.35 (m, 1H), 2.40 (s, 2H), 2.49-2.66 (m, 6H), 3.52 (s, 4H), 3.57(s, 2H), 3.62 (s, 2H), 6.94 (s, 2H), 7.15-7.46 (m, 9H).

Example 29(22)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.28 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.52-1.66 (m, 6H), 2.18 (s, 3H), 2.28-2.40 (m, 4H), 2.41(s, 2H), 2.58-2.66 (m, 2H), 3.42 (s, 2H), 3.60 (s, 4H), 3.63 (s, 2H),3.68 (s, 2H), 6.77 (d, J=5.1 Hz, 1H), 7.05 (s, 4H), 7.10 (d, J=5.1 Hz,1H), 7.24 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H).

Example 29(23)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.22-1.37 (m, 2H), 1.41-1.64 (m, 6H), 2.08-2.47 (m, 8H),3.41 (s, 2H), 3.59 (s, 4H), 3.61 (s, 2H), 3.62 (s, 2H), 6.84-6.88 (m,1H), 6.92 (dd, J=5.1, 3.6 Hz, 1H), 7.05 (s, 4H), 7.16-7.32 (m, 5H).

Example 29(24)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.22-1.37 (m, 2H), 1.40-1.67 (m, 6H), 2.12-2.45 (m, 8H),2.16 (s, 3H), 3.42 (s, 2H), 3.50 (s, 2H), 3.60 (s, 4H), 3.63 (s, 2H),6.77 (d, J=5.1 Hz, 1H), 7.05 (s, 4H), 7.08 (d, J=5.1 Hz, 1H), 7.23 (d,J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H).

Example 29(25)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.33 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.22-1.38 (m, 2H), 1.45-1.64 (m, 6H), 2.01-2.16 (m, 2H),2.25-2.45 (m, 6H), 3.39 (s, 2H), 3.62 (s, 4H), 3.65 (s, 4H), 6.83-6.86(m, 1H), 6.91 (dd, J=5.1, 3.3 Hz, 1H), 7.06 (s, 4H), 7.19 (dd, J=5.1,1.2 Hz, 1H), 7.24 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H).

Example 29(26)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-(1H-imidazol-2-ylmethyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine

Description: amorphous;

TLC: Rf 0.53 (chloroform:methanol:28% aqueous ammonia=90:10:2);

NMR (CD₃OD): δ 1.00-1.44 (m, 12H), 1.56-1.70 (m, 7H), 1.75-1.93 (m, 4H),2.21-2.34 (m, 1H), 2.34-2.66 (m, 10H), 3.23-3.40 (m, 2H), 3.57 (s, 4H),3.65 (s, 2H), 3.76-3.86 (m, 2H), 6.95 (s, 2H), 7.27 (d, J=9.00 Hz, 2H),7.33 (d, J=9.00 Hz, 2H).

Example 29(27)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-(1,3-oxazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.49 (chloroform:methanol:28% aqueous ammonia=90:10:2);

NMR (CD₃OD): δ 1.08-1.32 (m, 6H), 1.53-1.67 (m, 6H), 1.74-1.95 (m, 4H),2.16-2.31 (m, 1H), 2.38 (s, 2H), 2.43-2.63 (m, 6H), 3.56 (s, 2H), 3.61(s, 2H), 3.77 (s, 2H), 3.80 (s, 2H), 6.97 (s, 2H), 7.13 (d, J=0.9 Hz,1H), 7.26 (d, J=9.00 Hz, 2H), 7.32 (d, J=9.00 Hz, 2H), 7.87 (d, J=0.9Hz, 1H).

Example 29(28)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-(1,3-thiazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.51 (chloroform:methanol:28% aqueous ammonia=90:10:2);

NMR (CD₃OD): δ 0.94-1.35 (m, 6H), 1.42-1.68 (m, 6H), 1.70-1.93 (m, 4H),2.17-2.32 (m, 1H), 2.38 (s, 2H), 2.45-2.65 (m, 6H), 3.57 (s, 2H), 3.66(s, 2H), 3.78 (s, 2H), 3.92 (s, 2H), 6.98 (s, 2H), 7.29 (d, J=8.10 Hz,2H), 7.39 (d, J=8.10 Hz, 2H), 7.52 (d, J=3.3 Hz, 1H), 7.69 (d, J=3.3 Hz,1H).

Example 29(29)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(6-methyl-2-pyridinyl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.60 (chloroform:methanol:28% aqueous ammonia=90:10:2);

NMR (CD₃OD): δ 1.12-1.32 (m, 6H), 1.52-1.69 (m, 6H), 1.71-1.98 (m, 4H),2.19-2.33 (m, 1H), 2.38 (s, 2H), 2.48-2.66 (m, 6H), 2.50 (s, 3H), 3.55(s, 2H), 3.57 (s, 2H), 3.66 (s, 2H), 3.70 (s, 2H), 6.96 (s, 2H), 7.13(d, J=7.8 Hz, 1H), 7.25 (d, J=7.80 Hz, 2H), 7.32 (d, J=7.80 Hz, 2H),7.43 (d, J=7.8 Hz, 1H), 7.66 (t, J=7.8 Hz, 1H).

Example 29(30)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N,N-bis(2-pyridinylmethyl)methanamine

TLC: Rf 0.53 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 1.03-1.35 (m, 6H), 1.46-1.70 (m, 6H), 1.73-1.99 (m, 4H),2.26 (s, 1H), 2.38 (s, 2H), 2.46-2.68 (m, 6H), 3.56 (s, 2H), 3.65 (s,2H), 3.75 (s, 4H), 7.09-7.48 (m, 6H), 7.52-7.73 (m, 2H), 7.74-7.87 (m,2H), 8.26-8.53 (m, 2H).

Example 29(31)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.23 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.22-1.38 (m, 2H), 1.44-1.64 (m, 6H), 2.03-2.16 (m, 2H),2.14 (s, 3H), 2.24-2.47 (m, 6H), 3.40 (s, 2H), 3.54 (s, 2H), 3.62 (s,4H), 3.66 (s, 2H), 6.76 (d, J=4.8 Hz, 1H), 7.06 (s, 4H), 7.09 (d, J=4.8Hz, 1H), 7.21-7.33 (m, 4H).

Example 29(32)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.19 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.47-1.63 (m, 2H), 1.86-2.02 (m, 2H), 2.16 (s, 3H),2.21-2.27 (m, 2H), 2.28-2.55 (m, 6H), 3.45 (s, 2H), 3.51 (s, 2H), 3.59(s, 4H), 3.63 (s, 2H), 3.67-3.75 (m, 2H), 6.76 (d, J=5.1 Hz, 1H), 7.05(s, 4H), 7.08 (d, J=5.1 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1Hz, 2H).

Example 29(33)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.21 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.41-1.54 (m, 8H), 2.31-2.45 (m, 8H), 3.45 (s, 2H), 3.60(s, 4H), 3.64 (s, 2H), 3.71 (s, 2H), 6.87-6.90 (m, 1H), 6.93 (dd, J=5.1,3.6 Hz, 1H), 7.06 (s, 4H), 7.21 (dd, J=5.1, 1.2 Hz, 1H), 7.25 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4 Hz, 2H).

Example 29(34)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.16 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.41-1.53 (m, 8H), 2.18 (s, 3H), 2.31-2.46 (m, 8H), 3.45(s, 2H), 3.57-3.61 (m, 6H), 3.63 (s, 2H), 6.77 (d, J=5.1 Hz, 1H), 7.06(s, 4H), 7.11 (d, J=5.1 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1Hz, 2H).

Example 29(35)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.45-1.60 (m, 2H), 1.91-2.04 (m, 2H), 2.15-2.21 (m, 2H),2.28-2.43 (m, 4H), 2.49-2.61 (m, 2H), 3.39 (s, 2H), 3.60 (s, 4H), 3.64(s, 2H), 3.66-3.74 (m, 2H), 3.68 (s, 2H), 6.85-6.89 (m, 1H), 6.91 (dd,J=4.8, 3.6 Hz, 1H), 7.05 (s, 4H), 7.19 (dd, J=4.8, 1.2 Hz, 1H), 7.23 (d,J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H).

Example 29(36)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.23 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.42-1.60 (m, 2H), 1.90-2.05 (m, 2H), 2.16 (s, 3H), 2.18(s, 2H), 2.29-2.45 (m, 4H), 2.50-2.62 (m, 2H), 3.40 (s, 2H), 3.58 (s,2H), 3.60 (s, 4H), 3.64 (s, 2H), 3.67-3.76 (m, 2H), 6.75 (d, J=5.1 Hz,1H), 7.05 (s, 4H), 7.09 (d, J=5.1 Hz, 1H), 7.19-7.34 (m, 4H).

Example 29(37)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.71-1.93 (m, 4H), 2.39 (d, J=15.3 Hz, 1H), 2.42 (d,J=15.3 Hz, 1H), 2.49-2.71 (m, 6H), 3.52-3.56 (m, 2H), 3.59 (s, 4H), 3.61(s, 2H), 3.75 (d, J=13.8 Hz, 1H), 3.80 (d, J=13.8 Hz, 1H), 6.84-6.87 (m,1H), 6.90 (dd, J=5.1, 3.6 Hz, 1H), 7.03 (s, 4H), 7.17 (dd, J=5.1, 1.2Hz, 1H), 7.19-7.28 (m, 4H).

Example 29(38)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[4.4]non-2-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.31 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.71-1.94 (m, 4H), 2.16 (s, 3H), 2.39 (d, J=14.4 Hz, 1H),2.42 (d, J=14.4 Hz, 1H), 2.49-2.73 (m, 6H), 3.55 (s, 2H), 3.59 (s, 4H),3.62 (s, 2H), 3.69 (s, 2H), 6.75 (d, J=5.1 Hz, 1H), 7.04 (s, 4H), 7.07(d, J=5.1 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H).

Example 29(39)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.71-1.93 (m, 4H), 2.39 (d, J=15.3 Hz, 1H), 2.42 (d,J=15.3 Hz, 1H), 2.49-2.71 (m, 6H), 3.52-3.56 (m, 2H), 3.59 (s, 4H), 3.61(s, 2H), 3.75 (d, J=13.9 Hz, 1H), 3.80 (d, J=13.9 Hz, 1H), 6.84-6.87 (m,1H), 6.90 (dd, J=5.1, 3.6 Hz, 1H), 7.03 (s, 4H), 7.17 (dd, J=5.1, 1.2Hz, 1H), 7.19-7.28 (m, 4H).

Example 29(40)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[4.4]non-2-yl}methyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.31 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.71-1.94 (m, 4H), 2.16 (s, 3H), 2.39 (d, J=14.4 Hz, 1H),2.42 (d, J=14.4 Hz, 1H), 2.49-2.73 (m, 6H), 3.55 (s, 2H), 3.59 (s, 4H),3.62 (s, 2H), 3.69 (s, 2H), 6.75 (d, J=5.1 Hz, 1H), 7.04 (s, 4H), 7.07(d, J=5.1 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H).

Example 29(41)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-pyrrol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.54 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 1.10-1.38 (m, 6H), 1.54-1.71 (m, 6H), 1.74-1.95 (m, 4H),2.27-2.36 (m, 1H), 2.39 (s, 2H), 2.49-2.68 (m, 6H), 3.42 (s, 3H), 3.45(s, 2H), 3.49 (s, 2H), 3.57 (s, 2H), 3.60 (s, 2H), 5.87-5.94 (m, 1H),5.95-6.01 (m, 1H), 6.45-6.59 (m, 1H), 6.95 (s, 2H), 7.25 (s, 4H).

Example 29(42)1-{4-[(1′-cyclohexylspiro[indole-3,4′-piperidin]-1(2H)-yl)methyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.36 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.96-1.35 (m, 6H), 1.51-2.09 (m, 8H), 2.20-2.40 (m, 3H),2.81-2.97 (m, 2H), 3.22 (s, 2H), 3.61 (s, 4H), 3.67 (s, 2H), 4.27 (s,2H), 6.45 (d, J=7.8 Hz, 1H), 6.63-6.72 (m, 1H), 6.97-7.16 (m, 6H),7.22-7.42 (m, 4H).

Example 29(43)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-phenyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.62-1.77 (m, 6H), 2.42 (s, 2H), 2.56-2.65 (m, 2H),3.07-3.17 (m, 4H), 3.58 (s, 2H), 3.61 (s, 4H), 3.66 (s, 2H), 6.77-6.85(m, 1H), 6.89-6.97 (m, 2H), 7.07 (s, 4H), 7.19-7.37 (m, 6H).

Example 29(44)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.30 (ethyl acetate:methanol:28% aqueous ammonia=90:8:2);

NMR (CDCl₃): δ 1.52-1.66 (m, 6H), 2.30-2.45 (m, 6H), 2.58-2.67 (m, 2H),3.45 (s, 2H), 3.60 (s, 4H), 3.65 (s, 2H), 3.77 (s, 2H), 6.87-6.97 (m,2H), 7.03 (s, 4H), 7.19-7.34 (m, 5H).

Example 29(45)2-{[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)amino]methyl}-3-pyridinol

Description: amorphous;

TLC: Rf 0.28 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 1.02-1.37 (m, 6H), 1.58-1.72 (m, 6H), 1.72-2.01 (m, 4H),2.24-2.44 (m, 3H), 2.52-2.65 (m, 6H), 3.55 (s, 2H), 3.64 (s, 2H), 3.73(s, 2H), 3.87 (s, 2H), 6.99 (s, 2H), 7.10-7.22 (m, 1H), 7.21-7.40 (m,5H), 7.83-7.96 (m, 1H).

Example 29(46)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.41 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 1.02-1.33 (m, 6H), 1.53-1.68 (m, 6H), 1.73-1.94 (m, 4H),2.20-2.32 (m, 1H), 2.37 (s, 2H), 2.43-2.61 (m, 6H), 3.49 (s, 3H), 3.52(s, 2H), 3.56 (s, 2H), 3.61 (s, 2H), 3.65 (s, 2H), 6.83 (d, J=1.2 Hz,1H), 6.95 (d, J=1.2 Hz, 1H), 6.99 (s, 2H), 7.25 (s, 4H).

Example 29(47)4-{[8-(2-hydroxy-2-methylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.14 (s, 6H), 1.52-1.65 (m, 6H), 2.26 (s, 2H), 2.33 (s,2H), 2.44-2.60 (m, 6H), 3.57 (s, 2H), 4.60-4.73 (m, 4H), 6.95-7.10 (m,4H), 7.36 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H).

Example 29(48)4-{[8-(3-hydroxy-3-methylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.31 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20 (s, 6H), 1.50-1.65 (m, 8H), 2.20-2.61 (m, 10H), 3.56(s, 2H), 4.60-4.73 (m, 4H), 6.95-7.09 (m, 4H), 7.35 (d, J=8.1 Hz, 2H),7.56 (d, J=8.1 Hz, 2H).

Example 29(49) Methyl5-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}-2-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzoate

Description: amorphous;

TLC: Rf 0.50 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 1.37-1.54 (m, 6H), 2.10 (s, 3H), 2.18-2.35 (m, 6H),2.40 (t, J=6.6 Hz, 2H), 3.48 (s, 2H), 3.51 (s, 2H), 3.55 (s, 4H), 3.70(s, 2H), 3.76 (s, 3H), 6.78 (d, J=5.1 Hz, 1H), 6.81-7.20 (m, 4H), 7.25(d, J=5.1 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.49 (dd, J=7.8, 1.5 Hz, 1H),7.57 (d, J=1.5 Hz, 1H), 11.81-12.28 (m, 2H).

Example 29(50)2,2′-[({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}imino)bis(methylene)]di(3-pyridinol)

Description: amorphous;

TLC: Rf 0.34 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 0.95-1.36 (m, 6H), 1.48-1.68 (m, 6H), 1.71-1.96 (m, 4H),2.20-2.46 (m, 3H), 2.48-2.63 (m, 6H), 3.52 (s, 2H), 3.66 (s, 2H), 3.86(s, 4H), 6.86-7.44 (m, 8H), 7.81-8.09 (m, 2H).

Example 29(51)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-[(1-ethyl-1H-imidazol-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.46 (chloroform:methanol:28% aqueous ammonia=90:10:1);

NMR (CD₃OD): δ 1.17 (t, J=7.20 Hz, 3H), 1.19-1.34 (m, 6H), 1.62-1.70 (m,6H), 1.78-2.02 (m, 4H), 2.41 (s, 2H), 2.48-2.56 (m, 1H), 2.58-2.67 (m,2H), 2.67-2.82 (m, 4H), 3.53 (s, 2H), 3.59 (s, 2H), 3.60 (s, 2H), 3.64(s, 2H), 3.88 (q, J=7.20 Hz, 2H), 6.86 (m, 1H), 6.99-7.02 (m, 2H), 7.03(m, 1H), 7.22-7.36 (m, 4H).

Example 29(52)1-[4-({8-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.67 (dichrolomethane:methanol:28% aqueous ammonia=40:10:1);

NMR (CDCl₃): δ 1.53-1.65 (m, 6H), 2.30 (s, 3H), 2.31-2.43 (m, 6H),2.50-2.59 (m, 2H), 2.61 (s, 3H), 3.52 (s, 2H), 3.55 (s, 2H), 3.60 (s,4H), 3.64 (s, 2H), 7.07 (s, 4H), 7.21-7.35 (m, 4H).

Example 29(53)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isopropyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.80 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 1.02-1.28 (m, 6H), 1.37 (d, J=6.6 Hz, 6H), 1.52-1.68 (m,6H), 1.69-1.96 (m, 4H), 2.19-2.30 (m, 1H), 2.36 (s, 2H), 2.43-2.51 (m,4H), 2.55 (t, J=6.9 Hz, 2H), 3.47 (s, 2H), 3.57 (s, 2H), 3.60 (s, 2H),3.67 (s, 2H), 4.35 (m, 1H), 6.99 (d, J=1.2 Hz, 1H), 7.03 (d, J=1.2 Hz,1H), 7.05-7.17 (m, 2H), 7.25-7.62 (m, 4H), 12.43 (m, 1H).

Example 29(54)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.78 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.78 (d, J=6.6 Hz, 6H), 1.07-1.29 (m, 6H), 1.52-1.68 (m,6H), 1.73-2.01 (m, 5H), 2.19-2.29 (m, 1H), 2.35 (s, 2H), 2.40-2.51 (m,4H), 2.55 (t, J=6.6 Hz, 2H), 3.40 (s, 2H), 3.49 (s, 2H), 3.56 (s, 2H),3.61 (d, J=7.5 Hz, 2H), 3.66 (s, 2H), 6.87 (d, J=1.2 Hz, 1H), 7.01 (d,J=1.2 Hz, 1H), 7.02-7.16 (m, 2H), 7.22-7.36 (m, 4H), 12.47 (m, 1H).

Example 29(55)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.76 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 1.04-1.25 (m, 6H), 1.52-1.65 (m, 6H), 1.70-1.88 (m, 4H),2.16-2.26 (m, 1H), 2.30 (s, 2H), 2.40-2.50 (m, 4H), 2.53 (t, J=6.6 Hz,2H), 3.25-3.26 (m, 6H), 3.54 (s, 2H), 3.60 (s, 2H), 3.68 (s, 4H),6.77-6.79 (m, 2H), 6.89-6.95 (m, 2H), 7.09-7.19 (m, 2H), 7.20-7.26 (m,2H).

Example 29(56)1-{3-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.21 (dichrolomethane:methanol:28% aqueous ammonia=80:20:1);

NMR (CDCl₃): δ 0.99-1.30 (m, 6H), 1.41-2.01 (m, 10H), 2.13-2.82 (m,13H), 3.66 (s, 6H), 6.94-7.13 (m, 5H), 7.13-7.24 (m, 3H), 11.33-11.91(m, 2H).

Example 29(57)2-(2-{[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)amino]methyl}-1H-imidazol-1-yl)ethanol

Description: amorphous;

TLC: Rf 0.72 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.94-1.38 (m, 6H), 1.53-1.66 (m, 6H), 1.70-1.93 (m, 4H),2.19-2.33 (m, 1H), 2.35 (s, 2H), 2.42-2.52 (m, 4H), 2.56 (t, J=7.2 Hz,2H), 3.46 (s, 2H), 3.57 (s, 2H), 3.68 (s, 2H), 3.70 (s, 2H), 3.72-3.86(m, 4H), 6.94 (d, J=1.2 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H), 7.07-7.16 (m,2H), 7.28-7.42 (m, 4H), 12.19 (m, 1H).

Example 29(58)6-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}-2-[trans-4-(dipropylamino)cyclohexyl]-1-isoindolinone

Description: amorphous;

TLC: Rf 0.23 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.85 (t, J=7.2 Hz, 6H), 1.01-1.95 (m, 14H), 2.27-2.67(m, 4H), 2.80-3.03 (m, 1H), 3.56 (s, 4H), 3.92-4.10 (m, 1H), 4.38 (s,2H), 6.90-7.08 (m, 4H), 7.51 (d, J=7.8 Hz, 1H), 7.58 (dd, J=7.8, 1.5 Hz,1H), 7.74 (d, J=1.5 Hz, 1H).

Example 29(59)[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-cyclohexyl-2,8-diazaspiro[4.5]dec-3-yl]methanol

TLC: Rf 0.33 (28% aqueous ammonia:methanol:chloroform=2:13:90);

NMR (CDCl₃): δ 1.10-1.24 (m, 5H), 1.48-1.64 (m, 5H), 1.69-1.85 (m, 6H),2.12-2.27 (m, 2H), 2.37-2.51 (m, 4H), 2.68-2.81 (m, 1H), 2.90 (d, J=9.5Hz, 1H), 3.29-3.42 (m, 2H), 3.54-3.66 (m, 7H), 3.84 (d, J=13.5 Hz, 1H),7.05 (s, 4H), 7.18-7.24 (m, 2H), 7.27-7.32 (m, 2H).

Example 29(60)1-{4-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.53 (dichrolomethane:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 1.01-1.33 (m, 6H), 1.49-2.00 (m, 10H), 2.18-2.33 (m, 1H),2.41 (s, 2H), 2.44-2.56 (m, 4H), 2.56-2.68 (m, 4H), 2.72-2.83 (m, 2H),3.60 (s, 4H), 3.63 (s, 2H), 7.05 (s, 4H), 7.15 (d, J=8.1 Hz, 2H), 7.28(d, J=8.1 Hz, 2H).

Example 29(61)2-(2-{[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)amino]methyl}-1H-imidazol-1-yl)-N,N-dimethylacetamide

TLC: Rf 0.74 (chloroform:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CD₃OD): δ 0.84-1.40 (m, 6H), 1.37-1.71 (m, 6H), 1.72-1.99 (m, 4H),2.18-2.33 (m, 1H), 2.38 (s, 2H), 2.44-2.73 (m, 6H), 2.93 (s, 3H), 3.01(s, 3H), 3.40-3.72 (m, 8H), 4.61-4.94 (m, 2H), 6.76-7.05 (m, 4H),7.11-7.40 (m, 4H).

Example 30 Benzyl6-{[bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)amino]carbonyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a dichloromethane (3 mL) solution of2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid(188 mg), diisopropylethylamine (0.21 mL) andO-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (345 mg) were added. The reaction solution wasstirred for 30 minutes. To this solution, the compound (284 mg) obtainedin Example 3 was added. The reaction solution was stirred at roomtemperature for 16 hours. To the reaction solution, an aqueous 1N sodiumhydroxide solution (20 mL) was added. The aqueous layer was extractedtwice with dichloromethane (50 mL). The combined organic layer waswashed with saturated brine (20 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous sodium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (ethyl acetate: 10%-saturated aqueousammonia-methanol=1:0→10:1) to obtain the title compound (219 mg) havingthe following physical properties.

TLC: Rf 0.70 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 2.65 (s, 6H), 2.80 (m, 2H), 3.01 (s, 6H), 3.69 (t, J=6.0Hz, 2H), 4.62 (s, 2H), 5.02 (s, 2H), 5.04 (s, 2H), 5.18 (s, 2H), 6.99(m, 1H), 7.08 (m, 2H), 7.26 (m, 1H), 7.27 (m, 8H).

Example 31N,N-bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

To an ethanol (3 mL) solution of the compound (210 mg) obtained inExample 30, 10% palladium-carbon (21 mg) was added under an argonatmosphere. This solution was stirred under a hydrogen atmosphere forone hour. The reaction solution was filtrated through Celite (tradename), the filtrate was concentrated. Without purifying the residue, thetitle compound (158 mg) having the following physical properties wasobtained.

TLC: Rf 0.35 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 2.68 (s, 6H), 2.77 (t, J=5.7 Hz, 2H), 3.01 (s, 6H), 3.11(t, J=5.7 Hz, 2H), 3.94 (s, 2H), 5.04 (m, 4H), 6.97 (m, 2H), 6.99 (m,1H), 7.09 (m, 1H), 7.25 (m, 3H).

Example 32N,N-bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)-2-[4-(dipropylamino)cyclohexyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

The same operation as in Example 2 was performed, except for using thecompound (150 mg) obtained in Example 31 and4-(dipropylamino)cyclohexanone (269 mg), and then the obtained crudeproduct was purified by silica gel chromatography(dichrolomethane:methanol:28% aqueous ammonia=1:0:0→80:10:1) to obtainthe title compound (150 mg) having the following physical properties.

TLC: Rf 0.45 (chloroform:methanol:28% aqueous ammonia=80:10:1).

Example 332-[4-(dipropylamino)cyclohexyl]-N,N-bis(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydro-6-isoquinolinecarboxamide

The same operation as in Example 5, except for using the compound (190mg) obtained in Example 32, and then the obtained product was purifiedby silica gel chromatography (dichrolomethane:methanol:28% aqueousammonia=80:10:1→80:20:4) to obtain the following compound (91 mg).

Description: amorphous;

TLC: Rf 0.60 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (DMSO-d₆): δ 0.81 (t, J=7.5 Hz, 6H), 1.10-1.45 (m, 8H), 1.62-1.78(m, 2H), 1.78-1.93 (m, 2H), 2.18-2.44 (m, 6H), 2.69 (s, 4H), 3.65 (s,2H), 4.38-4.75 (m, 4H), 6.68-7.14 (m, 6H), 7.18 (dd, J=7.8, 1.5 Hz, 1H),11.87-12.72 (m, 2H).

Example 33(1)3-{1-[(1-cycloheptyl-4-piperidinyl)methyl]-4-piperidinyl}-N,N-bis(1H-imidazol-2-ylmethyl)propanamidediacetate

Except for using the corresponding carboxylic acid in place of2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acidin Example 30 and using the corresponding ketone in place of4-(dipropylamino) cyclohexanone in Example 32, the same operation as inExample 30→Example Example 32→Example 33 was performed to obtain thetitle compound having the following physical properties.

TLC: Rf 0.78 (chloroform:methanol:28% aqueous ammonia=40:10:2);

NMR (CD₃OD): δ 1.12-1.90 (m, 20H), 1.91 (s, 6H), 2.10-2.17 (m, 2H),2.23-2.37 (m, 2H), 2.38-2.52 (m, 2H), 2.51-2.61 (m, 1H), 2.72-2.89 (m,4H), 4.67 (s, 2H), 4.68 (s, 2H), 6.96 (s, 2H), 7.01 (s, 2H).

Example 344-({acetyl[trans-4-(dipropylamino)cyclohexyl]amino}methyl)-N,N-bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)benzamide

To a dichloromethane (3 mL) solution of the compound (150 mg) obtainedin Example 16 and triethylamine (59 μL), acetyl chloride (20 μL) wasadded at 0° C. The reaction solution was stirred at 0° C. for one hour.The reaction solution was diluted with dichloromethane (75 mL) and theorganic layer was washed in turn with an aqueous saturated sodiumhydrogen carbonate solution (20 mL) and saturated brine (20 mL), andthen dried over anhydrous magnesium sulfate. After removing theanhydrous sodium sulfate by filtration, the filtrate was concentrated.Without purifying the residue, the title compound (106 mg) having thefollowing physical properties was obtained.

TLC: Rf 0.43 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 0.86 (m, 6H), 1.38 (m, 6H), 1.68 (m, 4H), 2.23 (s, 3H),2.39 (m, 6H), 2.62 (s, 3H), 2.74 (s, 3H), 3.00 (m, 6H), 3.60 (m, 1H),4.47 (m, 3H), 5.03 (m, 4H), 6.98-7.61 (m, 8H).

Example 354-({acetyl[trans-4-(dipropylamino)cyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

The same operation as in Example 5 was performed, except for using thecompound obtained in Example 34 in Example 5, and then the obtainedcrude product was purified by silica gel chromatography(dichrolomethane:methanol:28% aqueous ammonia=10:1:0→80:10:1) to obtainthe title compound having the following physical properties.

Description: amorphous;

TLC: Rf 0.37 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.68-0.88 (m, 6H), 1.12-1.71 (m, 12H), 1.82-2.19 (m,3H), 2.19-2.44 (m, 5H), 3.55-4.35 (m, 1H), 4.36-4.67 (m, 6H), 6.75-7.11(m, 4H), 7.12-7.28 (m, 2H), 7.33-7.55 (m, 2H), 11.97-12.61 (m, 2H).

Example 35(1) to Example 35(2)

Except for using the corresponding chloride in place of acetyl chloride,the same operation as in Example 34→Example 35 was performed to obtainthe following compound.

Example 35(1)4-({benzoyl[trans-4-(dipropylamino)cyclohexyl]amino}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.36 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.62-0.80 (m, 6H), 0.81-1.02 (m, 2H), 1.09-1.40 (m,4H), 1.44-1.78 (m, 6H), 2.04-2.43 (m, 5H), 3.37-3.60 (m, 1H), 4.38-4.77(m, 6H), 6.74-7.17 (m, 4H), 7.20-7.65 (m, 9H), 11.91-12.58 (m, 2H).

Example 35(2)4-{[[trans-4-(dipropylamino)cyclohexyl](phenylacetyl)amino]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide

Description: amorphous;

TLC: Rf 0.41 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (DMSO-d₆): δ 0.79 (t, J=7.50 Hz, 6H), 1.06-1.84 (m, 12H), 2.02-2.46(m, 5H), 3.42-4.36 (m, 3H), 4.36-4.75 (m, 6H), 6.70-7.64 (m, 13H),11.84-12.74 (m, 2H).

Example 361-[4-(diethoxymethyl)phenyl]-N-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]methanamine

The same operation as in Example 2 was performed, except for using4-(diethoxymethyl)benzaldehyde in place of2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide and1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methanamine inplace of benzylamine, to obtain the title compound having the followingphysical properties.

TLC: Rf 0.63 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 7.43 (d, J=7.8 Hz, 2H), 7.33 (J=7.8 Hz, 2H), 6.97 (m,2H), 5.49 (s, 1H), 5.32 (s, 2H), 3.94 (s, 2H), 3.84 (s, 2H), 3.52 (m,6H), 1.24 (m, 6H), 0.88 (m, 2H), −0.03 (s, 9H).

Example 37N-[4-(diethoxymethyl)benzyl]-N-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1H-imidazole-2-carboxamide

The same operation as in Example 30 was performed, except for using thecompound (1.93 g) obtained in Example 36 and 1H-imidazole-2-carboxylicacid (773 mg), and then the obtained crude product was purified bysilica gel chromatography (ethyl acetate:methanol=1:0→10:1) to obtainthe title compound (977 mg) having the following physical properties.

TLC: Rf 0.44 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 7.41 (m, 4H), 7.15 (s, 2H), 7.04 (s, 1H), 6.96 (m, 1H),5.82 (s, 1H), 5.77 (s, 1H), 5.46 (s, 1H), 5.37 (s, 1H), 5.23 (s, 1H),4.83 (s, 1H), 4.76 (s, 1H), 3.51 (m, 6H), 1.25 (m, 6H), 0.82 (t, J=8.1Hz, 2H), −0.06 (s, 9H).

Example 38N-(4-formylbenzyl)-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

To the compound (970 mg) obtained in Example 37, a 50% trifluoroaceticacid-dichloromethane solution (10 mL) was added under ice cooling. Thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated and an aqueous 2N sodium hydroxidesolution (20 mL) was added to the residue. The aqueous layer wasextracted twice with dichloromethane (50 mL). The combined organic layerwas washed with saturated brine and then dried over anhydrous magnesiumsulfate to concentrate. Without purifying the residue, the obtainedresidue was used in the following reaction.

TLC: Rf 0.50 (chloroform:methanol:28% aqueous ammonia=80:10:1);

NMR (CDCl₃): δ 9.98 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz,2H), 7.23 (s, 2H), 7.08 (s, 2H), 5.04 (s, 2H), 4.87 (s, 2H).

Example 39N-(1H-imidazol-2-ylmethyl)-N-(4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzyl)-1H-imidazole-2-carboxamide

The same operation as in Example 2 was performed, except for using thecompound (107 mg) obtained in Example 38 in place of2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide, and2-(2-thienylmethyl)-2,7-diazaspiro[4.4]nonane (86 mg) in place ofbenzylamine, to obtain the title compound (97 mg) having the followingphysical properties.

Description: amorphous;

TLC: Rf 0.65 (chloroform:methanol:28% aqueous ammonia=40:9:1);

NMR (CDCl₃): δ 1.69-1.92 (m, 4H), 2.38-2.67 (m, 8H), 3.57 (s, 2H),3.77-3.81 (m, 2H), 4.75 (s, 2H), 4.95 (s, 2H), 6.86-6.89 (m, 1H), 6.91(dd, J=5.1, 3.6 Hz, 1H), 7.07 (s, 2H), 7.18 (s, 2H), 7.19 (dd, J=5.1,1.50 Hz, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 11.39 (s,1H), 12.17 (s, 1H).

Example 39(1) to Example 39(18)

The same operation as in Example 39 was carried out, except for using acorresponding amine in place of2-(2-thienylmethyl)-2,7-diazaspiro[4.4]nonane in Example 39, to obtainthe following compound.

Example 39(1)N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzyl]-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.56 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.53-1.75 (m, 6H), 2.18 (s, 3H), 2.28-2.40 (m, 4H), 2.41(s, 2H), 2.61 (t, J=6.6 Hz, 2H), 3.43 (s, 2H), 3.69 (s, 2H), 4.75 (s,2H), 4.95 (s, 2H), 6.77 (d, J=5.1 Hz, 1H), 7.07 (s, 2H), 7.10 (d, J=5.1Hz, 1H), 7.14-7.30 (m, 4H), 7.36 (d, J=8.1 Hz, 2H).

Example 39(2)N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.61 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.26-1.36 (m, 2H), 1.42-1.65 (m, 6H), 2.10-2.46 (m, 8H),3.43 (s, 2H), 3.62 (s, 2H), 4.74 (s, 2H), 4.95 (s, 2H), 6.86 (m, 1H),6.91 (dd, J=3.6, 5.1 Hz, 1H), 7.07, (s, 2H), 7.15-7.30 (m, 5H), 7.35 (d,J=8.4 Hz, 2H).

Example 39(3)N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.61 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.25-1.36 (m, 2H), 1.43-1.65 (m, 6H), 2.16 (s, 3H),2.20-2.47 (m, 8H), 3.43 (s, 2H), 3.50 (s, 2H), 4.74 (s, 2H), 4.95 (s,2H), 6.77 (d, J=5.1 Hz, 1H), 7.07 (s, 2H), 7.08 (d, J=5.1 Hz, 1H),7.15-7.30 (m, 4H), 7.35 (d, J=8.1 Hz, 2H).

Example 39(4)N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.63 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.26-1.38 (m, 2H), 1.46-1.62 (m, 6H), 2.03-2.16 (m, 2H),2.26-2.45 (m, 6H), 3.40 (s, 2H), 3.65 (s, 2H), 4.76 (s, 2H), 4.97 (s,2H), 6.85 (dd, J=1.2, 3.6 Hz, 1H), 6.91 (dd, J=3.6, 5.1 Hz, 1H), 7.08(s, 2H), 7.15-7.22 (m, 2H), 7.23-7.30 (m, 3H), 7.36 (d, J=8.1 Hz, 2H).

Example 39(5)N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzyl]-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.67 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.25-1.37 (m, 2H), 1.45-1.62 (m, 6H), 2.05-2.25 (m, 2H),2.14 (s, 3H), 2.26-2.44 (m, 6H), 3.40 (s, 2H), 3.54 (s, 2H), 4.75 (s,2H), 4.97 (s, 2H), 6.75 (d, J=5.1 Hz, 1H), 7.07 (s, 2H), 7.09 (d, J=5.1Hz, 1H), 7.18 (m, 1H), 7.24-7.30 (m, 3H), 7.37 (d, J=8.1 Hz, 2H).

Example 39(6)N-(1H-imidazol-2-ylmethyl)-N-[4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.62 (ethyl acetate:methanol:28% aqueous ammonia=50:10:1);

NMR (CDCl₃): δ 1.50-1.65 (m, 2H), 1.89-2.00 (m, 2H), 2.17 (s, 3H),2.22-2.40 (m, 4H), 2.40-2.52 (m, 4H), 3.46 (s, 2H), 3.52 (s, 2H), 3.72(t, J=4.5 Hz, 2H), 4.75 (s, 2H), 4.95 (s, 2H), 6.77 (d, J=5.1 Hz, 1H),7.07 (s, 2H), 7.10 (d, J=5.1 Hz, 1H), 7.14-7.30 (m, 4H), 7.35 (d, J=8.1Hz, 2H).

Example 39(7)N-[4-({[trans-4-(1-azepanyl)cyclohexyl]amino}methyl)benzyl]-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.48 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (CDCl₃): δ 1.05-1.41 (m, 4H), 1.51-1.70 (m, 8H), 1.81-2.09 (m, 4H),2.35-2.66 (m, 3H), 2.67-2.77 (m, 4H), 3.78 (s, 2H), 4.73 (s, 2H), 4.92(s, 2H), 7.07 (s, 2H), 7.18-7.30 (m, 4H), 7.34 (d, J=8.1 Hz, 2H), 12.28(s, 2H).

Example 39(8)N-[4-({[trans-4-(dipropylamino)cyclohexyl]amino}methyl)benzyl]-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.50 (chloroform:methanol:28% aqueous ammonia=80:20:1);

NMR (CDCl₃): δ 0.85 (t, J=7.5 Hz, 6H), 1.03-1.33 (m, 5H), 1.33-1.48 (m,4H), 1.72-1.86 (m, 2H), 1.94-2.07 (m, 2H), 2.30-2.56 (m, 6H), 3.79 (s,2H), 4.73 (s, 2H), 4.92 (s, 2H), 7.07 (s, 2H), 7.16-7.29 (m, 4H), 7.35(d, J=7.8 Hz, 2H), 12.21 (s, 2H).

Example 39(9)N-(1H-imidazol-2-ylmethyl)-N-[4-({[trans-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)cyclohexyl]amino}methyl)benzyl]-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.32 (chloroform:methanol:28% aqueous ammonia=80:20:1);

NMR (CDCl₃): δ 1.07-1.42 (m, 4H), 1.86-1.97 (m, 2H), 1.97-2.08 (m, 2H),2.10-2.18 (m, 1H), 2.21-2.30 (m, 4H), 2.38-2.50 (m, 1H), 2.53-2.65 (m,1H), 2.70-2.77 (m, 4H), 3.79 (s, 2H), 4.73 (s, 2H), 4.92 (s, 2H), 5.76(t, J=3.3 Hz, 2H), 7.07 (s, 2H), 7.20-7.29 (m, 4H), 7.35 (d, J=7.8 Hz,2H), 12.27 (s, 2H).

Example 39(10)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.46 (chloroform:methanol:28% aqueous ammonia=80:20:1);

NMR (CDCl₃): δ 1.03-1.58 (m, 7H), 1.61-1.75 (m, 1H), 1.80-1.95 (m, 6H),1.98-2.61 (m, 7H), 2.69-2.89 (m, 2H), 2.93-3.07 (m, 4H), 3.95 (s, 2H),4.70 (s, 2H), 4.95 (s, 2H), 7.09 (s, 2H), 7.25 (s, 2H), 7.31 (d, J=8.1Hz, 2H), 7.39 (d, J=8.1 Hz, 2H).

Example 39(11)N-(1H-imidazol-2-ylmethyl)-N-[4-({[trans-4-(1-piperidinyl)cyclohexyl]amino}methyl)benzyl]-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.27 (chloroform:methanol:28% aqueous ammonia=80:20:1);

NMR (CDCl₃): δ 1.05-1.51 (m, 6H), 1.54-1.69 (m, 4H), 1.84-2.10 (m, 4H),2.31-2.50 (m, 3H), 2.51-2.62 (m, 4H), 3.78 (s, 2H), 4.72 (s, 2H), 4.91(s, 2H), 7.07 (s, 2H), 7.21 (s, 2H), 7.24 (d, J=7.8 Hz, 2H), 7.34 (d,J=7.8 Hz, 2H), 12.52 (s, 2H).

Example 39(12)N-[4-({[trans-4-(1-azepanyl)cyclohexyl]amino}methyl)benzyl]-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.48 (chloroform:methanol:28% aqueous ammonia=80:20:4);

NMR (CDCl₃): δ 1.05-1.41 (m, 4H), 1.51-1.70 (m, 8H), 1.81-2.09 (m, 4H),2.35-2.66 (m, 3H), 2.67-2.77 (m, 4H), 3.78 (s, 2H), 4.73 (s, 2H), 4.92(s, 2H), 7.07 (s, 2H), 7.18-7.30 (m, 4H), 7.34 (d, J=8.1 Hz, 2H), 12.28(s, 2H).

Example 39(13)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide(low polar compound)

Description: amorphous;

TLC: Rf 0.75 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.82-2.08 (m, 25H), 2.03-2.69 (m, 11H), 4.00-4.33 (m,1H), 4.44-5.13 (m, 2H), 5.48-7.31 (m, 4H), 9.96-10.60 (m, 1H),12.13-12.66 (m, 1H).

Example 39(14)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide(high polar compound)

Description: amorphous;

TLC: Rf 0.75 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.80-2.04 (m, 25H), 2.09-2.68 (m, 11H), 4.14-4.45 (m,1H), 4.54-5.14 (m, 2H), 5.47-7.28 (m, 4H), 9.93-10.50 (m, 1H),12.31-12.71 (m, 1H).

Example 39(15)N-[trans-4-({[trans-4-(dipropylamino)cyclohexyl]amino}methyl)cyclohexyl]-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.18 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.86 (t, J=7.2 Hz, 6H), 0.96-1.19 (m, 4H), 1.20-1.50 (m,7H), 1.58-1.68 (m, 2H), 1.70-2.00 (m, 8H), 2.23-2.53 (m, 8H), 4.24 (m,1H), 4.64-5.02 (m, 2H), 6.94 (brs, 1H), 7.02 (s, 2H), 7.21 (s, 2H),12.35-12.44 (m, 2H).

Example 39(16)N-[trans-4-({[4-(dipropylamino)butyl]amino}methyl)cyclohexyl]-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.87 (t, J=7.2 Hz, 6H), 0.98-1.20 (m, 2H), 1.40-1.98 (m,15H), 2.34-2.51 (m, 8H), 2.56-2.64 (m, 2H), 4.25 (m, 1H), 4.64-5.06 (m,2H), 5.74 (m, 1H), 6.93-7.05 (m, 2H), 7.16-7.24 (m, 2H), 12.11-12.75 (m,2H).

Example 39(17)N-[trans-4-({[(4-hydroxy-1-methyl-4-piperidinyl)methyl]amino}methyl)cyclohexyl]-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.23 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.08 (m, 1H), 1.48-1.98 (m, 12H), 2.38-2.70 (m, 7H),2.70-2.84 (m, 2H), 2.98-3.10 (m, 2H), 4.22 (m, 1H), 4.60-5.00 (m, 2H),6.93-7.05 (m, 2H), 7.17-7.25 (m, 2H).

Example 39(18)N-({trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}methyl)-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide

Description: amorphous;

TLC: Rf 0.50 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.63-1.98 (m, 26H), 2.09-2.32 (m, 5H), 2.37-2.57 (m, 6H),3.37-4.40 (m, 2H), 4.61-5.09 (m, 2H), 6.89-7.07 (m, 2H), 7.14-7.35 (m,2H), 11.95-12.26 (m, 2H).

Example 40(1) to Example 40(79)

The same operation as in Example 4→Example 2→Example 5 was performed,except for using a corresponding carboxylic acid in place of4-formylbenzoic acid and a corresponding amine in place of2,2′-[iminobis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide inExample 4, and a corresponding amine was used in place of benzylamine inExample 2, to obtain the following compound.

Example 40(1)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 0.78 (d, J=6.6 Hz, 3H), 0.83 (d, J=6.6 Hz, 3H),1.33-1.83 (m, 7H), 1.86-2.45 (m, 6H), 3.15-3.63 (m, 10H), 6.80-6.90 (m,2H), 7.04-7.19 (m, 2H), 7.36-7.51 (m, 4H), 11.95-12.09 (m, 2H).

Example 40(2)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.35 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 1.35-1.81 (m, 6H), 2.04-2.57 (m, 7H), 3.17-3.65 (m,12H), 6.73-6.83 (m, 1H), 6.83-6.89 (m, 2H), 7.08-7.17 (m, 2H), 7.21-7.32(m, 1H), 7.37-7.50 (m, 4H), 12.03 (s, 2H).

Example 40(3)1-(4-{[8-(2-ethylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 0.72-0.86 (m, 6H), 1.13-1.80 (m, 11H), 1.95-2.46 (m,6H), 3.16-3.66 (m, 10H), 6.77-6.94 (m, 2H), 7.06-7.18 (m, 2H), 7.39-7.49(m, 4H), 11.97-12.12 (m, 2H).

Example 40(4)1-{4-[(8-cyclopentyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.18 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 1.09-1.85 (m, 14H), 2.06-2.58 (m, 5H), 3.14-3.62 (m,10H), 6.77-6.92 (m, 2H), 7.04-7.18 (m, 2H), 7.38-7.48 (m, 4H),12.00-12.18 (m, 2H).

Example 40(5)1-(4-{[8-(cyclohexylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.42 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 0.62-1.79 (m, 17H), 1.92-2.44 (m, 6H), 3.14-3.71 (m,10H), 6.78-6.94 (m, 2H), 7.04-7.19 (m, 2H), 7.36-7.52 (m, 4H),11.94-12.12 (m, 2H).

Example 40(6)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[8-(2-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.44 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 1.34-1.82 (m, 6H), 2.07-2.66 (m, 7H), 3.18-3.66 (m,12H), 6.77-7.28 (m, 8H), 7.38-7.51 (m, 4H), 11.96-12.08 (m, 2H).

Example 40(7)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]-N,N-bis(1H-imidazol-2-ylmethyl)cyclohexanamine

Description: amorphous;

TLC: Rf 0.37 (chloroform:methanol:28% aqueous ammonia=90:13:2);

NMR (CDCl₃): δ 1.14-1.92 (m, 24H), 2.24-2.67 (m, 7H), 3.21-3.56 (m, 4H),3.79-4.41 (m, 4H), 6.83-7.05 (m, 4H).

Example 40(8)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.31 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 0.74-0.88 (m, 9H), 1.34-1.79 (m, 6H), 1.91-2.06 (m,2H), 2.15-2.60 (m, 4H), 3.16-3.66 (m, 10H), 6.79-6.91 (m, 2H), 7.06-7.18(m, 2H), 7.37-7.51 (m, 4H), 11.97-12.11 (m, 2H).

Example 40(9)1-{4-[(9-cyclohexyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.22 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.00-1.34 (m, 6H), 1.35-1.70 (m, 8H), 1.70-1.92 (m, 4H),2.25 (m, 1H), 2.44-2.60 (m, 4H), 3.39-3.42 (m, 2H), 3.54 (s, 4H), 3.58(s, 2H), 3.64-3.80 (m, 2H), 7.01 (s, 4H), 7.25 (d, J=8.1 Hz, 2H), 7.32(d, J=8.1 Hz, 2H), 11.20-12.11 (m, 2H).

Example 40(10)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]carbonyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.34-1.68 (m, 8H), 2.40-2.52 (m, 4H), 3.30-3.40 (m, 2H),3.53 (s, 4H), 3.57 (s, 2H), 3.67-3.80 (m, 4H), 6.89 (dd, J=3.6, 1.2 Hz,1H), 6.94 (dd, J=5.1, 3.6 Hz, 1H), 7.00 (s, 4H), 7.22 (dd, J=5.1, 1.2Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H).

Example 40(11)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.34-1.68 (m, 8H), 2.19 (s, 3H), 2.39-2.52 (m, 4H),3.28-3.40 (m, 2H), 3.53 (s, 4H), 3.56 (s, 2H), 3.62 (s, 2H), 3.65-3.80(m, 2H), 6.78 (d, J=5.1 Hz, 1H), 7.00 (s, 4H), 7.12 (d, J=5.1 Hz, 1H),7.25 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H).

Example 40(12)1-{trans-4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]cyclohexyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.47 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.75-2.10 (m, 25H), 2.16-2.72 (m, 8H), 3.29-3.26 (m, 2H),3.42-3.58 (m, 2H), 3.61 (s, 4H), 7.03 (s, 4H).

Example 40(13)1-{4-[(8-cycloheptyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.14 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 1.16-1.78 (m, 18H), 2.12-2.60 (m, 5H), 3.15-3.62 (m,10H), 6.82-6.88 (m, 2H), 7.09-7.15 (m, 2H), 7.39-7.49 (m, 4H),11.97-12.09 (m, 2H).

Example 40(14)1-(4-{[8-(cyclopentylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.15 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 0.96-1.81 (m, 15H), 1.95-2.59 (m, 6H), 3.17-3.65 (m,10H), 6.82-6.88 (m, 2H), 7.09-7.15 (m, 2H), 7.39-7.49 (m, 4H),11.99-12.11 (m, 2H).

Example 40(15)1-(4-{[8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.15 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ −0.06-0.12 (m, 2H), 0.32-0.51 (m, 2H), 0.61-0.93 (m,1H), 1.35-1.81 (m, 6H), 2.03-2.62 (m, 6H), 3.16-3.66 (m, 10H), 6.78-6.91(m, 2H), 7.05-7.19 (m, 2H), 7.36-7.52 (m, 4H), 12.00-12.14 (m, 2H).

Example 40(16)1-{4-[(2-cyclohexyl-2,7-diazaspiro[3.5]non-7-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.88-1.30 (m, 6H), 1.50-1.90 (m, 8H), 1.97 (m, 1H), 3.04(s, 4H), 3.24-3.42 (m, 2H), 3.54 (s, 4H), 3.59 (s, 2H), 3.60-3.77 (m,2H), 7.02 (s, 4H), 7.26 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H).

Example 40(17)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-2-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.76-1.88 (m, 4H), 2.17 (s, 3H), 2.28-2.52 (m, 4H), 3.57(s, 2H), 3.58 (s, 4H), 3.62 (s, 2H), 3.89 (s, 2H), 3.98 (s, 2H), 6.78(d, J=5.1 Hz, 1H), 7.02 (s, 4H), 7.11 (d, J=5.1 Hz, 1H), 7.38 (d, J=8.1Hz, 2H), 7.53 (d, J=8.1 Hz, 2H).

Example 40(18)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.64-1.92 (m, 4H), 2.19 (s, 3H), 3.11 (s, 4H), 3.24-3.40(m, 2H), 3.54 (s, 4H), 3.59 (s, 2H), 3.60-3.80 (m, 4H), 6.79 (d, J=5.1Hz, 1H), 7.02 (s, 4H), 7.11 (d, J=5.1 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H),7.34 (d, J=8.1 Hz, 2H).

Example 40(19)1-{4-[(7-cyclohexyl-2,7-diazaspiro[3.5]non-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-yl)methyl)methanamine

Description: amorphous;

TLC: Rf 0.25 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.00-1.32 (m, 6H), 1.62 (m, 1H), 1.70-1.90 (m, 7H), 2.26(m, 1H), 2.40-2.57 (m, 4H), 3.59 (s, 4H), 3.64 (s, 2H), 3.88 (s, 2H),3.97 (s, 2H), 7.04 (s, 4H), 7.41 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz,2H).

Example 40(20)1-{4-[(9-cyclohexyl-2,9-diazaspiro[5.5]undec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.25 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.96-2.78 (m, 23H), 3.17 (m, 1H), 3.33 (m, 1H), 3.48-3.80(m, 8H), 7.03 (s, 4H), 7.23-7.30 (m, 2H), 7.35 (d, J=8.1 Hz, 2H),11.30-12.11 (m, 2H).

Example 40(21)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.22-1.48 (m, 2H), 1.60-1.98 (m, 2H), 2.08-2.63 (m, 7H),3.18-3.85 (m, 14H), 6.77 (d, J=5.1 Hz, 1H), 7.06 (s, 4H), 7.11 (d, J=5.1Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H).

Example 40(22)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(7-isobutyl-2,7-diazaspiro[3.5]non-2-yl)carbonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.70-1.88 (m, 5H), 1.97-2.04 (m,2H), 2.18-2.40 (m, 4H), 3.59 (s, 4H), 3.63 (s, 2H), 3.86 (s, 2H), 3.97(s, 2H), 7.03 (s, 4H), 7.40 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H).

Example 40(23)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(2-isobutyl-2,7-diazaspiro[3.5]non-7-yl)carbonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.50-1.90 (m, 5H), 2.24-2.30 (m,2H), 3.03 (s, 4H), 3.25-3.40 (m, 2H), 3.50-3.74 (m, 8H), 7.04 (s, 4H),7.28 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H).

Example 40(24)1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.58 (dichrolomethane:methanol:28% aqueous ammonia=40:10:1);

NMR (DMSO-d₆): δ 0.73-0.91 (m, 6H), 1.09-1.82 (m, 10H), 1.97-2.65 (m,5H), 3.13-3.67 (m, 10H), 6.78-6.91 (m, 2H), 7.04-7.19 (m, 2H), 7.36-7.51(m, 4H), 11.97-12.13 (m, 2H).

Example 40(25)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-isopropyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.22 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.98-1.10 (m, 6H), 1.50-1.88 (m, 6H), 2.25-2.80 (m, 5H),3.22-3.74 (m, 10H), 7.03 (s, 4H), 7.32-7.44 (m, 4H).

Example 40(26)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(9-isobutyl-2,9-diazaspiro[5.5]undec-2-yl)carbonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.25 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.72-0.98 (m, 6H), 1.20-2.54 (m, 15H), 3.12-3.40 (m, 2H),3.45-3.80 (m, 8H), 7.04 (s, 4H), 7.27 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1Hz, 2H).

Example 40(27)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.22-1.72 (m, 8H), 2.00-2.65 (m, 7H), 3.10-3.80 (m, 12H),6.76 (m, 1H), 7.04 (s, 4H), 7.09 (m, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.35(d, J=8.1 Hz, 2H).

Example 40(28)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.88 (d, J=6.6 Hz, 6H), 1.32-1.68 (m, 8H), 1.77 (m, 1H),2.06 (d, J=7.5 Hz, 2H), 2.26-2.43 (m, 4H), 3.30-3.41 (m, 2H), 3.54 (s,4H), 3.58 (s, 2H), 3.66-3.78 (m, 2H), 7.02 (s, 4H), 7.26 (d, J=8.1 Hz,2H), 7.33 (d, J=8.1 Hz, 2H).

Example 40(29)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.78-0.98 (m, 6H), 1.35 (m, 1H), 1.64-1.92 (m, 4H),1.98-2.58 (m, 6H), 3.18-3.88 (m, 12H), 7.05 (s, 4H), 7.27 (d, J=8.1 Hz,2H), 7.37 (d, J=8.1 Hz, 2H).

Example 40(30)1-{4-[(9-cyclohexyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.22 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.00-1.98 (m, 14H), 2.25 (m, 1H), 2.40-2.68 (m, 4H),3.15-3.84 (m, 12H), 7.06 (s, 4H), 7.29 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1Hz, 2H), 10.91-11.62 (m, 2H).

Example 40(31)1-(1H-imidazol-2-yl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.55 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.85 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.40-1.91(m, 7H), 2.02 (d, J=7.2 Hz, 1H), 2.08 (d, J=7.2 Hz, 1H), 2.12-2.56 (m,4H), 3.26 (s, 1H), 3.44-3.53 (m, 4H), 3.55-3.63 (m, 5H), 3.65-3.76 (m,3H), 6.89 (s, 1H), 7.01 (s, 1H), 7.08 (s, 1H), 7.13 (s, 1H), 7.38-7.55(m, 4H), 12.28-12.50 (m, 1H).

Example 40(32)1-(1H-imidazol-2-yl)-N-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]benzyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.61 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.78-0.92 (m, 6H), 1.13-1.90 (m, 5H), 1.94-2.58 (m, 6H),3.08-3.85 (m, 8H), 3.49 (s, 2H), 3.60 (s, 3H), 3.71 (s, 2H), 6.89 (d,J=1.2 Hz, 1H), 7.02 (d, J=1.2 Hz, 1H), 7.09 (s, 1H), 7.13 (s, 1H), 7.37(d, J=7.8 Hz, 2H), 7.48 (d, J=7.8 Hz, 2H), 12.29-12.50 (m, 1H).

Example 40(33)1-(1H-imidazol-2-yl)-N-{4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]benzyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.66 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.88 (d, J=6.6 Hz, 6H), 1.32-1.64 (m, 8H), 1.67-1.84 (m,1H), 2.07 (d, J=7.2 Hz, 2H), 2.28-2.38 (m, 4H), 3.30-3.42 (m, 2H), 3.48(s, 2H), 3.59 (s, 3H), 3.59-3.60 (m, 2H), 3.64-3.76 (m, 4H), 6.89 (d,J=1.2 Hz, 1H), 7.01 (d, J=1.2 Hz, 1H), 7.09 (s, 1H), 7.13 (s, 1H), 7.37(d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 12.40 (s, 1H).

Example 40(34)1-{4-[(9-cyclopentyl-2,9-diazaspiro[5.5]undec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.18 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.19-1.96 (m, 16H), 2.09-2.78 (m, 5H), 3.18 (m, 1H), 3.33(m, 1H), 3.47-3.80 (m, 8H), 7.04 (s, 4H), 7.26-7.31 (m, 2H), 7.35 (d,J=8.4 Hz, 2H).

Example 40(35)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(tetrahydro-2H-pyran-4-yl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.18 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-1.83 (m, 12H), 2.10-2.78 (m, 5H), 3.10-3.80 (m,12H), 3.85-4.08 (m, 2H), 7.04 (s, 4H), 7.25-7.30 (m, 2H), 7.35 (d, J=8.1Hz, 2H).

Example 40(36)1-[4-({8-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}carbonyl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.22 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (DMSO-d₆): δ 1.33-1.80 (m, 6H), 2.11-2.59 (m, 10H), 3.18-3.64 (m,12H), 6.80-6.90 (m, 2H), 7.08-7.17 (m, 2H), 7.38-7.50 (m, 4H),12.00-12.10 (m, 2H).

Example 40(37)1-(4-{[9-(2-ethylbutyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.23 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.70-0.90 (m, 6H), 1.10-1.72 (m, 13H), 1.80-2.52 (m, 6H),3.18 (m, 1H), 3.32 (m, 1H), 3.45-3.80 (m, 8H), 7.04 (s, 4H), 7.26 (d,J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H).

Example 40(38)1-(4-{[9-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.23 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.70-0.90 (m, 9H), 1.20-1.70 (m, 8H), 1.82 (m, 1H),1.95-2.20 (m, 2H), 2.30 (m, 1H), 2.42-2.60 (m, 2H), 3.18 (m, 1H), 3.31(m, 1H), 3.45-3.78 (m, 8H), 7.03 (s, 4H), 7.25 (d, J=8.1 Hz, 2H),7.28-7.35 (m, 2H).

Example 40(39)1-(4-{[9-(cyclohexylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.23 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.70-0.95 (m, 2H), 1.05-1.80 (m, 17H), 1.85-2.20 (m, 4H),2.33 (m, 1H), 2.46 (m, 1H), 3.17 (m, 1H), 3.32 (m, 1H), 3.48-3.80 (m,8H), 7.03 (s, 4H), 7.25 (d, J=7.8 Hz, 2H), 7.33 (d, J=7.8 Hz, 2H).

Example 40(40)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-methylbenzyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.36 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.18-1.75 (m, 8H), 1.95-2.59 (m, 7H), 3.10-3.80 (m, 12H),7.02 (s, 4H), 7.04-7.18 (m, 4H), 7.24 (d, J=8.1 Hz, 2H), 7.26-7.38 (m,2H).

Example 40(41)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methoxy-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-1.72 (m, 8H), 2.08-2.35 (m, 2H), 2.40-2.64 (m, 2H),3.15 (m, 1H), 3.31 (m, 1H), 3.40-3.75 (m, 10H), 3.79 (s, 3H), 6.79 (m,1H), 7.03 (s, 4H), 7.09 (m, 1H), 7.24 (d, J=7.8 Hz, 2H), 7.33 (d, J=7.8Hz, 2H).

Example 40(42)1-(4-{[9-(1-ethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.68-0.95 (m, 6H), 1.05-1.72 (m, 12H), 1.90-2.20 (m, 2H),2.30 (m, 1H), 2.40-2.60 (m, 2H), 3.18 (m, 1H), 3.32 (m, 1H), 3.45-3.64(m, 7H), 3.72 (m, 1H), 7.01 (s, 4H), 7.24 (d, J=7.8 Hz, 2H), 7.33 (d,J=7.8 Hz, 2H).

Example 40(43)1-{4-[(9-cycloheptyl-2,9-diazaspiro[5.5]undec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-2.04 (m, 20H), 2.24-2.83 (m, 5H), 3.15 (m, 1H), 3.35(m, 1H), 3.50-3.78 (m, 8H), 7.03 (s, 4H), 7.25-7.32 (m, 2H), 7.38 (d,J=7.5 Hz, 2H).

Example 40(44)(2-{[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}-3-thienyl)methanol

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.05-1.72 (m, 8H), 2.10-2.80 (m, 4H), 3.08 (m, 1H),3.25-3.75 (m, 11H), 4.45-4.65 (m, 2H), 6.96 (d, J=5.1 Hz, 1H), 7.03 (s,4H), 7.08 (d, J=5.1 Hz, 1H), 7.25 (d, J=7.5 Hz, 2H), 7.36 (d, J=7.5 Hz,2H).

Example 40(45)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.11 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-2.70 (m, 18H), 2.90-3.78 (m, 13H), 7.04 (s, 4H),7.29 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H).

Example 40(46)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(tetrahydro-2H-thiopyran-4-yl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.21 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-1.80 (m, 12H), 1.90 (m, 1H), 2.05-2.28 (m, 2H), 2.35(m, 1H), 2.50-2.76 (m, 5H), 3.17 (m, 1H), 3.33 (m, 1H), 3.45-3.64 (m,7H), 3.72 (m, 1H), 7.04 (s, 4H), 7.23-7.30 (m, 2H), 7.37 (d, J=7.8 Hz,2H).

Example 40(47)1-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.49 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.85 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.3 Hz, 3H), 1.43-1.85(m, 7H), 1.94-2.58 (m, 6H), 3.21 (s, 1H), 3.32 (s, 6H), 3.40-3.52 (m,2H), 3.62-3.75 (m, 7H), 6.80 (s, 2H), 6.94 (s, 2H), 7.22-7.30 (m, 2H),7.39-7.48 (m, 2H).

Example 40(48)1-{4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.49 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.89 (d, J=6.3 Hz, 6H), 1.30-1.64 (m, 8H), 1.69-1.86 (m,1H), 2.08 (d, J=7.2 Hz, 2H), 2.26-2.42 (m, 4H), 3.33 (s, 8H), 3.69 (s,8H), 6.80 (s, 2H), 6.93 (s, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1Hz, 2H).

Example 40(49)1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.26 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.72-0.97 (m, 6H), 1.15-1.90 (m, 8H), 2.00-2.65 (m, 5H),3.22 (m, 1H), 3.35-3.88 (m, 11H), 7.05 (s, 4H), 7.28 (d, J=8.1 Hz, 2H),7.37 (d, J=8.1 Hz, 2H), 10.70-12.06 (m, 2H).

Example 40(50)1-(4-{[9-(2-ethylbutyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.28 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.75-0.93 (m, 6H), 1.16-1.45 (m, 7H), 1.60-1.90 (m, 2H),2.00-2.53 (m, 6H), 3.23 (m, 1H), 3.67-3.85 (m, 11H), 7.06 (s, 4H), 7.29(d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H).

Example 40(51)1-(4-{[9-(2,2-dimethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.28 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.73-0.95 (m, 9H), 1.24-1.45 (m, 2H), 1.40-1.90 (m, 2H),1.94-2.12 (m, 2H), 2.30-2.63 (m, 4H), 3.24 (m, 1H), 3.35-3.88 (m, 11H),7.06 (s, 4H), 7.28 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H).

Example 40(52)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methoxy-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}carbonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.24-1.46 (m, 2H), 1.63-1.94 (m, 2H), 2.22-2.69 (m, 4H),3.21 (m, 1H), 3.32-3.86 (m, 16H), 6.08 (d, J=5.4 Hz, 1H), 7.06 (s, 4H),7.10 (d, J=5.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H).

Example 40(53)(2-{[4-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl]methyl}-3-thienyl)methanol

Description: amorphous;

TLC: Rf 0.22 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.08-1.30 (m, 2H), 1.80-1.95 (m, 2H), 2.25-2.70 (m, 4H),3.17 (m, 1H), 3.35-3.85 (m, 13H), 4.55 (s, 2H), 6.96 (d, J=5.1 Hz, 1H),7.05 (s, 4H), 7.09 (d, J=5.1 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.37 (d,J=7.8 Hz, 2H).

Example 40(54)1-{4-[(9-cycloheptyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.18 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-1.93 (m, 16H), 2.34-2.65 (m, 5H), 3.20 (m, 1H),3.33-3.85 (m, 11H), 7.06 (s, 4H), 7.28 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1Hz, 2H), 10.82-11.81 (m, 2H).

Example 40(55)1-{4-[(9-cyclopentyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.18 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.22-1.98 (m, 12H), 2.26 (m, 1H), 3.22 (m, 1H), 3.35-3.88(m, 11H), 7.06 (s, 4H), 7.29 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H).

Example 40(56)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}benzyl)methanamine

Description: amorphous;

TLC: Rf 0.18 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.20-1.95 (m, 8H), 2.33-2.65 (m, 5H), 3.15-3.85 (m, 14H),3.92-4.06 (m, 2H), 7.05 (s, 4H), 7.28 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1Hz, 2H).

Example 40(57)1-(4-{[9-(cyclohexylmethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.72-0.94 (m, 2H), 1.05-1.90 (m, 13H), 1.98-2.52 (m, 6H),3.22 (m, 1H), 3.30-3.85 (m, 11H), 7.05 (s, 4H), 7.27 (d, J=7.8 Hz, 2H),7.36 (d, J=7.8 Hz, 2H).

Example 40(58)1-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

Description: amorphous;

TLC: Rf 0.59 (ethyl acetate:methanol:28% aqueous ammonia=40:10:2);

NMR (CDCl₃): δ 0.86 (s, 6H), 1.16-1.93 (m, 5H), 1.95-2.54 (m, 6H),3.05-3.87 (m, 6H), 3.34 (s, 6H), 3.69 (s, 6H), 6.80 (d, J=1.2 Hz, 2H),6.94 (d, J=1.2 Hz, 2H), 7.22-7.38 (m, 4H).

Example 40(59)1-{4-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.98-1.32 (m, 6H), 1.40-1.97 (m, 10H), 2.13-2.67 (m, 5H),3.24-3.66 (m, 12H), 7.02 (s, 4H), 7.11-7.18 (m, 2H), 7.22-7.30 (m, 2H),10.84-12.01 (m, 2H).

Example 40(60)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[2-(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]benzyl}methanamine

TLC: Rf 0.43 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.83-0.91 (m, 6H), 1.48-1.86 (m, 7H), 2.01-2.07 (m, 2H),2.11-2.51 (m, 4H), 3.25-3.66 (m, 12H), 7.02 (s, 4H), 7.11-7.19 (m, 2H),7.23-7.31 (m, 2H), 10.60-12.03 (m, 2H).

Example 40(61)1-(4-{[7-(1-ethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.87 (t, J=7.5 Hz, 6H), 1.19-1.50 (m, 4H), 1.68-1.82 (m,4H), 2.13 (m, 1H), 2.32-2.50 (m, 4H), 3.59 (s, 4H), 3.62 (s, 2H), 3.87(s, 2H), 3.96 (s, 2H), 7.02 (s, 4H), 7.39 (d, J=8.1 Hz, 2H), 7.55 (d,J=8.1 Hz, 2H).

Example 40(62)1-(4-{[7-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.84 (s, 9H), 1.68-1.85 (m, 4H), 2.00 (s, 2H), 2.32-2.52(m, 4H), 3.59 (s, 4H), 3.63 (s, 2H), 3.87 (s, 2H), 3.96 (s, 2H), 7.03(s, 4H), 7.40 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H).

Example 40(63)1-(4-{[2-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-7-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.19 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.85 (s, 9H), 1.60-1.92 (m, 4H), 2.21 (s, 2H), 3.07 (s,4H), 3.22-3.40 (m, 2H), 3.54 (s, 4H), 3.58 (s, 2H), 3.62-3.78 (m, 2H),7.01 (s, 4H), 7.25 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H).

Example 40(64)1-(4-{[9-(1-ethylpropyl)-3,9-diazaspiro[5.5]undec-3-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.26 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.89 (t, J=7.5 Hz, 6H), 1.21-1.63 (m, 12H), 2.13 (m, 1H),2.40-2.52 (m, 4H), 3.30-3.40 (m, 2H), 3.54 (s, 4H), 3.58 (s, 2H),3.65-3.80 (m, 2H), 7.01 (s, 4H), 7.26 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1Hz, 2H).

Example 40(65)1-{3-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.41 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.97-1.34 (m, 6H), 1.44-1.92 (m, 10H), 2.15-2.73 (m, 5H),3.24-3.76 (m, 10H), 7.03 (s, 4H), 7.28-7.43 (m, 3H), 7.66-7.72 (m, 1H).

Example 40(66)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{3-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}methanamine

TLC: Rf 0.46 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.85 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.47-1.88(m, 7H), 1.97-2.56 (m, 6H), 3.25-3.75 (m, 10H), 7.03 (s, 4H), 7.28-7.42(m, 3H), 7.66-7.72 (m, 1H).

Example 40(67)1-(4-{[9-(2,2-dimethylpropyl)-3,9-diazaspiro[5.5]undec-3-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.26 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.85 (s, 9H), 1.35-1.64 (m, 8H), 2.03 (s, 2H), 2.40-2.52(m, 4H), 3.30-3.40 (m, 2H), 3.54 (s, 4H), 3.57 (s, 2H), 3.65-3.80 (m,2H), 7.00 (s, 4H), 7.26 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H).

Example 40(68)1-(4-{2-[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-2-oxoethyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.35 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.79-0.90 (m, 9H), 1.43-1.60 (m, 4H), 1.67-1.83 (m, 2H),1.97-2.03 (m, 2H), 2.26-2.58 (m, 4H), 3.25-3.66 (m, 12H), 7.03 (s, 4H),7.11-7.19 (m, 2H), 7.21-7.31 (m, 2H).

Example 40(69)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[2-(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)-1,1-dimethyl-2-oxoethyl]benzyl}methanamine

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.75-0.90 (m, 6H), 0.96-1.84 (m, 13H), 1.90-2.42 (m, 6H),2.59-3.59 (m, 4H), 3.59-3.69 (m, 6H), 7.03-7.10 (m, 4H), 7.16-7.41 (m,4H).

Example 40(70)1-(4-{2-[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-2-oxoethyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.25 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.88 (t, J=7.4 Hz, 6H), 1.18-1.57 (m, 8H), 1.66-1.84 (m,2H), 2.06-2.19 (m, 1H), 2.26-2.57 (m, 4H), 3.26-3.35 (m, 2H), 3.48-3.57(m, 2H), 3.59 (s, 6H), 3.62 (s, 2H), 7.02 (s, 4H), 7.11-7.20 (m, 2H),7.23-7.31 (m, 2H).

Example 40(71)2-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)ethanamine

TLC: Rf 0.19 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.97-1.35 (m, 6H), 1.46-2.00 (m, 10H), 2.12-2.90 (m, 9H),3.20-3.75 (m, 8H), 7.01 (s, 4H), 7.11-7.19 (m, 2H), 7.33-7.41 (m, 2H).

Example 40(72)1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.80-0.96 (m, 6H), 1.18-1.82 (m, 10H), 2.13 (m, 1H),2.26-2.60 (m, 4H), 3.21-3.74 (m, 13H), 6.88 (m, 1H), 7.01 (m, 1H), 7.08(m, 1H), 7.13 (m, 1H), 7.40-7.51 (m, 4H).

Example 40(73)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.80-0.88 (m, 9H), 1.48-1.85 (m, 6H), 1.97-2.07 (m, 2H),2.27-2.60 (m, 4H), 3.22-3.73 (m, 13H), 6.89 (s, 1H), 7.00 (s, 1H), 7.07(m, 1H), 7.13 (m, 1H), 7.40-7.50 (m, 4H).

Example 40(74)1-(4-{[9-(2,2-dimethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.72-0.92 (m, 9H), 1.60-1.85 (m, 4H), 1.90-2.10 (m, 2H),2.27-2.62 (m, 4H), 3.15-3.85 (m, 15H), 6.89 (m, 1H), 7.01 (m, 1H), 7.08(m, 1H), 7.13 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H).

Example 40(75)1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.72-0.95 (m, 6H), 1.15-1.85 (m, 8H), 2.10 (m, 1H),2.22-2.62 (m, 4H), 3.15-3.85 (m, 15H), 6.89 (m, 1H), 7.01 (m, 1H), 7.08(m, 1H), 7.13 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H).

Example 40(76)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.42 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.84 (d, J=6.6 Hz, 6H), 0.91-1.38 (m, 6H), 1.38-2.86 (m,16H), 3.20-3.32 (m, 1H), 3.36-3.54 (m, 5H), 3.57-3.74 (m, 6H), 6.83-6.94(m, 1H), 6.98-7.05 (m, 1H), 7.05-7.18 (m, 2H), 7.34-7.60 (m, 4H).

Example 40(77)1-(1H-imidazol-2-yl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.35 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.72-0.99 (m, 12H), 1.29-2.68 (m, 14H), 2.92-3.32 (m,1H), 3.37-3.57 (m, 5H), 3.57-3.82 (m, 6H), 6.85-6.93 (m, 1H), 6.97-7.07(m, 1H), 7.10 (s, 2H), 7.33-7.56 (m, 4H).

Example 40(78)1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.37 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.73-1.04 (m, 12H), 1.09-2.72 (m, 16H), 3.05-3.28 (m,1H), 3.33-3.55 (m, 5H), 3.57-3.88 (m, 6H), 6.84-6.93 (m, 1H), 6.98-7.06(m, 1H), 7.10 (s, 2H), 7.34-7.60 (m, 4H).

Example 40(79)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.50 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.65-0.97 (m, 15H), 1.29-1.89 (m, 6H), 1.89-2.17 (m, 3H),2.20-2.68 (m, 4H), 3.17-3.32 (m, 1H), 3.34-3.55 (m, 5H), 3.57-3.82 (m,6H), 6.85-6.93 (m, 1H), 6.98-7.06 (m, 1H), 7.11 (s, 2H), 7.36-7.52 (m,4H).

Examples 41(1) to Example 41(3)

The same operation as in Example 4→Example 2→Example 5 was performed,except for using a corresponding amine in place of the compound obtainedin Example 3 in Example 19, and a corresponding amine in place ofbenzylamine in Example 2, to obtain the following compound.

Example 41(1)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)sulfonyl]benzyl}methanamine

Description: amorphous;

TLC: Rf 0.35 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.84 (d, J=6.6 Hz, 6H), 1.24-1.45 (m, 4H), 1.63 (t, J=7.2Hz, 2H), 1.63-1.78 (m, 1H), 1.99 (d, J=7.2 Hz, 2H), 2.02-2.37 (m, 4H),3.08 (s, 2H), 3.28 (t, J=7.2 Hz, 2H), 3.58 (s, 4H), 3.73 (s, 2H), 7.09(s, 4H), 7.56 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H).

Example 41(2)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}sulfonyl)benzyl]methanamine

Description: amorphous;

TLC: Rf 0.36 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.27-1.46 (m, 4H), 1.63 (t, J=7.2 Hz, 2H), 2.12-2.49 (m,4H), 2.15 (s, 3H), 3.08 (s, 2H), 3.28 (t, J=7.2 Hz, 2H), 3.54 (s, 2H),3.57 (s, 4H), 3.72 (s, 2H), 6.76 (d, J=5.1 Hz, 1H), 7.09 (s, 4H), 7.10(d, J=5.1 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H).

Example 41(3)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)sulfonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

Description: amorphous;

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.00-1.43 (m, 10H), 1.62 (t, J=7.2 Hz, 2H), 1.68-1.84 (m,4H), 2.12-2.57 (m, 5H), 3.08 (s, 2H), 3.28 (t, J=7.2 Hz, 2H), 3.59 (s,4H), 3.74 (s, 2H), 7.10 (s, 4H), 7.58 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7Hz, 2H), 10.43-11.18 (m, 2H).

Example 42 Tert-butyl2-[4-(methoxycarbonyl)benzyl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

Under an argon atmosphere, to an N,N-dimethylformamide (2 mL) solutionof sodium hydride (60%, 94 mg), an N,N-dimethylformamide (4 mL) solutionof tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (514 mg) wasadded at 0° C. The reaction solution was stirred at 50° C. for one hour.The solution was cooled to 0° C. and then an N,N-dimethylformamide (2mL) solution of methyl 4-(bromomethyl)benzoate (442 mg) was added. Thereaction solution was stirred at 0° C. for 30 minutes. To the reactionsolution, 0.5N-hydrochloric acid (20 mL) was added. The aqueous layerwas extracted twice with ethyl acetate. The aqueous layer was combinedwith the organic layer, washed in turn with water and saturated brine,and then dried over anhydrous magnesium sulfate. After removing theanhydrous magnesium sulfate by filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (n-hexane:ethyl acetate=1:0→1:2) to obtain the titlecompound (553 mg) having the following physical properties.

Description: amorphous;

TLC: Rf 0.51 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.99 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 4.49 (m,2H), 3.91 (s, 3H), 3.42 (m, 2H), 3.27 (m, 2H), 3.03 (s, 2H), 2.37 (s,2H), 1.51 (m, 4H), 1.43 (s, 9H).

Example 43 Tert-butyl2-[4-(hydroxymethyl)benzyl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

Under an argon atmosphere, to an anhydrous tetrahydrofuran (3 mL)solution of the compound (453 mg) obtained by the previous reaction,lithium borohydride (26 mg) was added. The reaction solution was stirredat 50° C. for 3 hours. The reaction solution was cooled to roomtemperature and an aqueous 0.5N-sodium hydroxide solution (10 mL) wasadded. The aqueous layer was extracted twice with ethyl acetate. Thecombined organic layer was washed with saturated brine and then driedover anhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography(n-hexane:ethyl acetate=1:0→1:4) to obtain the title compound (365 mg)having the following physical properties.

TLC: Rf 0.18 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 7.33 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 4.68 (d,J=5.7 Hz, 2H), 4.43 (s, 2H), 3.44 (m, 2H), 3.23 (m, 2H), 3.03 (s, 2H),2.36 (s, 2H), 1.51 (m, 4H), 1.43 (s, 9H).

Example 44 Tert-butyl2-(4-formylbenzyl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

To a dimethyl sulfoxide (7.5 mL)-ethyl acetate (1.5 mL) solution of thecompound (332 mg) obtained in Example 43 and triethylamine (1.85 mL), adimethyl sulfoxide (1.5 mL) solution of a sulfur trioxide-pyridinecomplex (430 mg) was added. The reaction solution was stirred at roomtemperature for 30 minutes. To the reaction solution, water (30 mL) wasadded. The aqueous layer was extracted twice with ethyl acetate. Theaqueous layer was combined with the organic layer, washed in turn withwater, 0.5N-hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and saturated brine, and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (n-hexane:ethylacetate=1:0→0:1) to obtain the title compound (335 mg) having thefollowing physical properties.

TLC: Rf 0.38 (ethyl acetate);

NMR (CDCl₃): δ 10.01 (s, 1H), 7.87 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz,2H), 4.53 (s, 2H), 3.46 (m, 2H), 3.25 (m, 2H), 3.07 (s, 2H), 2.39 (s,2H), 1.51 (m, 4H), 1.44 (s, 9H).

Example 45 Tert-butyl2-(4-{[bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)amino]methyl}benzyl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

With the compound (330 mg) produced in Example 44 and the compound (525mg) produced in Example 3, the same operation as in Example 2 wasperformed to obtain the title compound (486 mg) having the followingphysical properties.

Description: amorphous;

TLC: Rf 0.19 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 7.31 (d, J=8.1 Hz, 2H), 7.23 (d, J=1.5 Hz, 2H), 7.13 (d,J=8.1 Hz, 2H), 6.99 (d, J=1.5 Hz, 2H), 4.41 (s, 2H), 4.16 (s, 4H), 4.06(s, 2H), 3.44 (m, 2H), 3.25 (m, 2H), 3.02 (s, 2H), 2.81 (s, 12H), 2.35(s, 2H), 1.52 (m, 4H), 1.44 (s, 9H).

Example 462-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-2,8-diazaspiro[4.5]decan-3-one

A 2N-hydrochloric acid (5 mL) solution of the compound (480 mg) obtainedin Example 45 was stirred at 80° C. for 3 hours. After the reactionsolution was cooled to room temperature, the pH was adjusted to 12 withan aqueous 2N-sodium hydroxide solution. The aqueous layer was extractedfour times with dichloromethane. The combined organic layer was washedwith saturated brine and then dried over anhydrous magnesium sulfate.After removing the anhydrous magnesium sulfate by filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate:10%-saturatedaqueous ammonia-methanol=1:0→7:3) to obtain the title compound (277 mg)having the following physical properties.

Description: amorphous;

TLC: Rf 0.32 (dichrolomethane:methanol:28% aqueous ammonia=70:30:3);

NMR (CDCl₃): δ 7.35 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.05 (s,4H), 4.42 (s, 2H), 3.63 (s, 2H), 3.60 (s, 4H), 3.07 (s, 2H), 2.77 (t,J=5.1 Hz, 4H), 2.37 (s, 2H), 1.52 (m, 4H).

Example 472-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-isobutyl-2,8-diazaspiro[4.5]decan-3-one

With the compound (50 mg) produced in Example 46 and isobutyl aldehyde(47 mg), the same operation as in Example 2 was performed to obtain thetitle compound (29 mg, 51%) having the following physical properties.

Description: amorphous;

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.86 (d, J=6.6 Hz, 6H), 1.54-1.64 (m, 4H), 1.65-1.82 (m,1H), 2.02 (d, J=7.2 Hz, 2H), 2.20-2.35 (m, 4H), 2.34 (s, 2H), 3.05 (s,2H), 3.60 (s, 4H), 3.65 (s, 2H), 4.42 (s, 2H), 7.07 (s, 4H), 7.16 (d,J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H).

Example 48(1) to Example 48(14)

Except for using the corresponding carbonyl in Example 47 in place ofisobutyl aldehyde, the same operation as in Example 47 was performed toobtain the following compound.

Example 48(1)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-cyclohexyl-2,8-diazaspiro[4.5]decan-3-one

Description: amorphous;

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.00-1.33 (m, 6H), 1.54-1.68 (m, 4H), 1.70-1.88 (m, 4H),2.17-2.31 (m, 1H), 2.33 (s, 2H), 2.38-2.59 (m, 4H), 3.05 (s, 2H), 3.60(s, 4H), 3.63 (s, 2H), 4.42 (s, 2H), 7.05 (s, 4H), 7.14 (d, J=8.1 Hz,2H), 7.34 (d, J=8.1 Hz, 2H).

Example 48(2)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decan-3-one

Description: amorphous;

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.55-1.66 (m, 4H), 2.16 (s, 3H), 2.26-2.51 (m, 4H), 2.34(s, 2H), 3.05 (s, 2H), 3.57 (s, 2H), 3.59 (s, 4H), 3.63 (s, 2H), 4.42(s, 2H), 6.77 (d, J=5.1 Hz, 1H), 7.06 (s, 4H), 7.11 (d, J=5.1 Hz, 1H),7.15 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H).

Example 48(3)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]decan-3-one

TLC: Rf 0.34 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.82 (s, 9H), 1.50-1.61 (m, 4H), 1.99 (s, 2H), 2.33 (s,2H), 2.36-2.46 (m, 4H), 3.05 (s, 2H), 3.59 (s, 4H), 3.63 (s, 2H), 4.41(s, 2H), 7.05 (s, 4H), 7.13 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H).

Example 48(4)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decan-3-one

TLC: Rf 0.16 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (t, J=7.4 Hz, 6H), 1.16-1.49 (m, 4H), 1.49-1.65 (m,4H), 2.05-2.17 (m, 1H), 2.33 (s, 2H), 2.36-2.47 (m, 4H), 3.05 (s, 2H),3.59 (s, 4H), 3.62 (s, 2H), 4.41 (s, 2H), 7.05 (s, 4H), 7.13 (d, J=8.1Hz, 2H), 7.33 (d, J=8.1 Hz, 2H).

Example 48(5)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-cyclohexyl-2,8-diazaspiro[4.5]decan-1-one

TLC: Rf 0.28 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 1.01-2.10 (m, 16H), 2.20-2.41 (m, 3H), 2.83-2.96 (m, 2H),3.13-3.22 (m, 2H), 3.58 (s, 4H), 3.61 (s, 2H), 4.41 (s, 2H), 7.06 (s,4H), 7.09 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H).

Example 48(6)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-isobutyl-2,8-diazaspiro[4.5]decan-1-one

TLC: Rf 0.33 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.90 (d, J=6.6 Hz, 6H), 1.35-1.47 (m, 2H), 1.70-1.86 (m,1H), 1.86-2.13 (m, 8H), 2.76-2.86 (m, 2H), 3.14-3.22 (m, 2H), 3.59 (s,4H), 3.60 (s, 2H), 4.42 (s, 2H), 7.06 (s, 4H), 7.09 (d, J=8.1 Hz, 2H),7.31 (d, J=8.1 Hz, 2H).

Example 48(7)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]decan-1-one

TLC: Rf 0.42 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.87 (s, 9H), 1.29-1.40 (m, 2H), 1.87-1.97 (m, 2H),1.98-2.13 (m, 4H), 2.20-2.35 (m, 2H), 2.72-2.84 (m, 2H), 3.12-3.22 (m,2H), 3.60 (s, 4H), 3.61 (s, 2H), 4.42 (s, 2H), 7.07 (s, 4H), 7.10 (d,J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H).

Example 48(8)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decan-1-one

TLC: Rf 0.41 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.90 (t, J=7.4 Hz, 6H), 1.21-1.56 (m, 6H), 1.86-2.07 (m,4H), 2.10-2.22 (m, 1H), 2.29-2.43 (m, 2H), 2.64-2.78 (m, 2H), 3.13-3.21(m, 2H), 3.59 (s, 4H), 3.61 (s, 2H), 4.41 (s, 2H), 7.06 (s, 4H), 7.09(d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H).

Example 48(9)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-cyclohexyl-2,9-diazaspiro[5.5]undecan-1-one

TLC: Rf 0.16 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.97-1.38 (m, 6H), 1.43-1.97 (m, 10H), 2.17-2.39 (m, 3H),2.39-2.61 (m, 2H), 2.78-2.93 (m, 2H), 3.15-3.24 (m, 2H), 3.55 (s, 4H),3.57 (s, 2H), 4.52 (s, 2H), 7.03 (d, J=8.1 Hz, 2H), 7.04 (s, 4H), 7.22(d, J=8.1 Hz, 2H).

Example 48(10)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-isobutyl-2,9-diazaspiro[5.5]undecan-1-one

TLC: Rf 0.26 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.90 (d, J=6.6 Hz, 6H), 1.45-1.58 (m, 2H), 1.70-1.88 (m,4H), 2.03-2.42 (m, 7H), 2.66-2.78 (m, 2H), 3.16-3.25 (m, 2H), 3.57 (s,4H), 3.58 (s, 2H), 4.52 (s, 2H), 7.02-7.10 (m, 6H), 7.21-7.28 (m, 2H).

Example 48(11)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undecan-1-one

TLC: Rf 0.37 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.86 (s, 9H), 1.39-1.51 (m, 2H), 1.68-1.88 (m, 4H), 2.05(s, 2H), 2.24-2.47 (m, 4H), 2.64-2.75 (m, 2H), 3.16-3.24 (m, 2H), 3.57(s, 4H), 3.58 (s, 2H), 4.52 (s, 2H), 7.07 (d, J=8.1 Hz, 2H), 7.05 (s,4H), 7.23 (d, J=8.1 Hz, 2H).

Example 48(12)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-(1-ethylpropyl)-2,9-diazaspiro[5.5]undecan-1-one

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.90 (t, J=7.3 Hz, 6H), 1.18-1.89 (m, 10H), 2.08-2.33 (m,3H), 2.39-2.55 (m, 2H), 2.57-2.72 (m, 2H), 3.16-3.24 (m, 2H), 3.57 (s,4H), 3.60 (s, 2H), 4.52 (s, 2H), 7.04-7.09 (m, 6H), 7.21-7.27 (m, 2H).

Example 48(13)3-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-cyclohexyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.97-1.99 (m, 14H), 2.23-2.40 (m, 1H), 2.49-2.77 (m, 4H),3.13 (s, 2H), 3.60 (s, 4H), 3.64 (s, 2H), 4.40 (s, 2H), 7.06 (s, 4H),7.19 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H).

Example 48(14)3-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(1-ethylpropyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

TLC: Rf 0.27 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.87 (t, J=7.3 Hz, 6H), 1.19-1.52 (m, 4H), 1.60-1.74 (m,2H), 1.82-1.94 (m, 2H), 2.10-2.22 (m, 1H), 2.36-2.49 (m, 2H), 2.61-2.74(m, 2H), 3.14 (s, 2H), 3.60 (s, 4H), 3.63 (s, 2H), 4.40 (s, 2H), 7.06(s, 4H), 7.18 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H).

Example 49 Tert-butyl(dimethyl)[2-(4-methylphenyl)ethoxy]silane

To N,N-dimethylformamide (6 mL) solution of 2-(4-bromophenyl)ethanol(552 mg), imidazole (248 mg) and tert-butyldimethylsilyl chloride (453mg) were added. The reaction solution was stirred at room temperaturefor 3 hours. To the reaction solution, 1N-hydrochloric acid (10 mL) wasadded. The aqueous layer was extracted twice with ethyl acetate. Thecombined organic layer was washed with water and saturated brine andthen dried over anhydrous magnesium sulfate. After removing theanhydrous magnesium sulfate by filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (n-hexane:ethyl acetate=1:0→97:3) to obtain the titlecompound (829 mg) having the following physical properties.

TLC: Rf 0.51 (n-hexane:ethyl acetate=50:1);

NMR (CDCl₃): δ 7.39 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 3.77 (t,J=6.9 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 0.86 (s, 9H), −0.03 (s, 6H).

Example 50 Tert-butyl2-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2,8-diazaspiro[4.5]decane-8-carboxylate

Under an argon atmosphere, an anhydrous toluene (1 mL) solution oftrisdibenzylideneacetone dipalladium (21 mg),biphenyl-2-yl(dicyclohexyl)phosphine (32 mg) and tert-butoxy potassium(306 mg) was stirred at room temperature for one hour. To this solution,an anhydrous toluene (2 mL) solution of the compound (714 mg) obtainedin Example 49 and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate(594 mg) was added. The reaction solution was stirred at 100° C. for onehour. The reaction solution was cooled to room temperature, and thenwater (10 mL) was added. The aqueous layer was filtered through Celite(trade name). The aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed with saturated brine and then driedover anhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography(n-hexane:ethyl acetate=98:2→77:23) to obtain the title compound (683mg) having the following physical properties.

TLC: Rf 0.24 (n-hexane:ethyl acetate=19:1);

NMR (CDCl₃): δ 7.07 (d, J=8.4 Hz, 2H), 6.48 (d, J=8.4 Hz, 2H), 3.73 (t,J=6.9 Hz, 2H), 3.49 (m, 2H), 3.36 (m, 4H), 3.14 (s, 2H), 2.73 (t, J=6.9Hz, 2H), 1.87 (t, J=6.9 Hz, 2H), 1.56 (m, 4H), 1.46 (s, 9H), 0.89 (s,9H), −0.03 (s, 6H).

Example 51 Tert-butyl2-[4-(2-hydroxyethyl)phenyl]-2,8-diazaspiro[4.5]decane-8-carboxylate

To a tetrahydrofuran (4 mL) solution of the compound (657 mg) obtainedin Example 50, a tetrahydrofuran solution (1.0N, 2.8 mL) oftetrabutylammonium fluoride was added. The reaction solution was stirredat room temperature for 4 hours. To the reaction solution, saturatedbrine (10 mL) was added. The aqueous layer was extracted with ethylacetate. The combined organic layer was washed with saturated brine andthen dried over anhydrous magnesium sulfate. After removing theanhydrous magnesium sulfate by filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (n-hexane:ethyl acetate=67:33→36:67) to obtain the titlecompound (423 mg) having the following physical properties.

TLC: Rf 0.44 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.09 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 3.80 (dt,J=6.6, 6.6 Hz, 2H), 3.49 (m, 2H), 3.37 (m, 4H), 3.15 (s, 2H), 2.77 (t,J=6.6 Hz, 2H), 1.88 (t, J=6.9 Hz, 2H), 1.56 (m, 4H), 1.47 (s, 9H).

Example 52 Tert-butyl2-[4-(2-oxoethyl)phenyl]-2,8-diazaspiro[4.5]decane-8-carboxylate

The same operation as in Example 44 was performed, except for using thecompound (210 mg) obtained in Example 51 in place of the compoundobtained in Example 43, to obtain the title compound (73 mg) having thefollowing physical properties.

TLC: Rf 0.80 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 9.69 (t, J=2.7 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.54 (d,J=8.4 Hz, 2H), 3.57 (d, J=2.7 Hz, 2H), 3.48 (m, 2H), 3.37 (m, 4H), 3.16(s, 2H), 1.89 (t, J=6.9 Hz, 2H), 1.56 (m, 4H), 1.47 (s, 9H).

Example 53 Tert-butyl2-(4-{2-[bis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)amino]ethyl}phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

The same operation as in Example 2 was performed, except for using thecompound (71 mg) obtained in Example 52 in place of the compoundobtained in Example 1, and the compound (102 mg) obtained in Example 3in place of benzylamine in Example 2, to obtain the title compound (131mg) having the following physical properties.

TLC: Rf 0.43 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 7.26 (m, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.65 (m, 2H), 6.45(d, J=8.4 Hz, 2H), 4.20 (s, 4H), 3.48 (m, 2H), 3.32 (m, 4H), 3.12 (s,2H), 2.93 (m, 2H), 2.87 (s, 12H), 2.76 (m, 2H), 1.86 (t, J=6.9 Hz, 2H),1.57 (m, 4H), 1.46 (s, 9H).

Example 542-[4-(2,8-diazaspiro[4.5]dec-2-yl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)ethanamine

The same operation as in Example 46 was performed, except for using thecompound (166 mg) obtained in Example 53 in place of the compoundobtained in Example 45 in Example 46, to obtain the title compound (92mg) having the following physical properties.

TLC: Rf 0.21 (dichrolomethane:methanol:28% aqueous ammonia=40:10:1);

NMR (CDCl₃): δ 7.06 (d, J=8.4 Hz, 2H), 7.00 (s, 4H), 6.49 (d, J=8.4 Hz,2H), 3.66 (s, 4H), 3.32 (t, J=6.9 Hz, 2H), 3.14 (s, 2H), 2.81 (m, 8H),1.84 (t, J=6.9 Hz, 2H), 1.57 (m, 4H)

Example 552-[4-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)ethanamine

The same operation as in Example 2 was performed, except for using thecompound (62 mg) obtained in Example 54 and cyclohexanone (21 mg), toobtain the title compound (36 mg) having the following physicalproperties.

Description: amorphous;

TLC: Rf 0.20 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.03-1.35 (m, 6H), 1.53-1.95 (m, 10H), 2.19-2.88 (m, 9H),3.09 (s, 2H), 3.26-3.35 (m, 2H), 3.66 (s, 4H), 6.44-6.52 (m, 2H), 6.99(s, 4H), 7.01-7.09 (m, 2H).

Example 55(1)2-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)ethanamine

The same operation as in Example 50→Example 51→Example 52→Example53→Example 54→Example 55 was performed, except for using a correspondingalcohol in place of 4-(2-hydroxyethyl)bromobenzene in Example 49, toobtain the title compound (36 mg) having the following physicalproperties.

Description: amorphous;

TLC: Rf 0.22 (dichrolomethane:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.03-1.37 (m, 6H), 1.52-1.98 (m, 10H), 2.24-2.41 (m, 1H),2.43-2.72 (m, 4H), 2.74-2.92 (m, 4H), 3.09 (s, 2H), 3.30 (t, J=6.9 Hz,2H), 3.68 (s, 4H), 6.35-6.45 (m, 2H), 6.47-6.55 (m, 1H), 6.99 (s, 4H),7.15 (t, J=7.8 Hz, 1H).

Example 56N,N-dimethyl-2-({[(1-methyl-1H-imidazol-2-yl)methyl]amino}methyl)-1H-imidazole-1-sulfonamide

To a 1% acetic acid-dimethylformamide (40 mL) solution of benzylamine(2.32 g) and 2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.00 g)synthesized in Example 1, sodium triacetoxyborohydride (4.18 g) wasadded. The reaction solution was stirred at room temperature for 15hours. To the reaction solution, an aqueous 5N-sodium hydroxide solutionwas added, followed by extraction twice with dichloromethane. Theorganic layer was washed with saturated brine and then dried overanhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated. The residue waspurified by silica gel chromatography (n-hexane:ethyl acetate=4:1→ethylacetate:methanol=9:1). To a 1% acetic acid-dimethylformamide (40 mL)solution of the obtained compound and1-methyl-1H-imidazole-2-carbaldehyde (2.38 g), sodiumtriacetoxyborohydride (4.18 g) was added. The reaction solution wasstirred at room temperature for 15 hours. To the reaction solution, anaqueous 5N-sodium hydroxide solution was added, followed by extractiontwice with dichloromethane. The organic layer was washed with saturatedbrine and then dried over anhydrous magnesium sulfate. After removingthe anhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(ethyl acetate:methanol=9:1→ethyl acetate:methanol: 28% aqueousammonia=29:1:0.2) to obtain a compound (3.10 g). The same operation asin Example 3, except for using the obtained compound, and then theobtained crude product was purified by silica gel chromatography (ethylacetate:methanol=9:1) to obtain the title compound (1.66 g) having thefollowing physical properties.

TLC: Rf 0.54 (ethyl acetate:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 2.88 (s, 6H), 3.69 (s, 3H), 3.94 (s, 2H), 4.07 (s, 2H),6.82 (d, J=1.3 Hz, 1H), 6.89 (d, J=1.3 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H),7.23 (d, J=1.7 Hz, 1H).

Example 574-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

The same operation as in Example 4→Example 5→Example 8 was performed,except for using the amine obtained in Example 56 in place of2,2′-[iminobis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)in Example 4, to obtain the title compound having the following physicalproperties.

TLC: Rf 0.33 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (DMSO-d₆): δ 0.80 (s, 9H), 1.37-1.57 (m, 6H), 1.95 (s, 2H),2.23-2.55 (m, 6H), 2.27 (s, 2H), 3.52 (s, 3H), 3.57-3.77 (m, 2H),4.36-4.80 (m, 4H), 6.77-6.96 (m, 2H), 7.00-7.14 (m, 2H), 7.28 (d, J=8.1Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 12.07-12.44 (m, 1H).

Example 57(1) to Example 57(7)

The same operation as in Example 56→Example 57 was performed, except forusing a corresponding aldehyde in place of1-methyl-1H-imidazole-2-carbaldehyde in Example 56, and a correspondingamine in place of 8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]decane inExample 57, to obtain the following compound.

Example 57(1)N-(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,8-diazaspiro[4.5]dec-8-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.24 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (DMSO-d₆): δ 0.83 (d, J=6.6 Hz, 6H), 1.36-1.55 (m, 6H), 1.55-1.72(m, 1H), 2.07 (d, J=7.5 Hz, 2H), 2.18-2.34 (m, 6H), 2.37-2.46 (m, 2H),3.41 (s, 3H), 3.57-3.75 (m, 2H), 4.39-4.78 (m, 4H), 6.79-6.94 (m, 2H),7.00-7.15 (m, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.35-7.50 (m, J=8.1 Hz, 2H),12.05-12.47 (m, 1H).

Example 57(2)4-{[2-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.23 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (DMSO-d₆): δ 0.83 (s, 9H), 1.36-1.58 (m, 6H), 2.14 (s, 2H),2.17-2.35 (m, 4H), 2.40 (s, 2H), 2.54-2.65 (m, 2H), 3.41 (s, 3H),3.52-3.77 (m, 2H), 4.34-4.80 (m, 4H), 6.78-6.94 (m, 2H), 7.01-7.16 (m,2H), 7.28 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 12.09-12.48 (m,1H).

Example 57(3)4-{[2-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.25 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (DMSO-d₆): δ 0.78 (t, J=7.4 Hz, 6H), 1.20-1.56 (m, 10H), 1.91-2.03(m, 1H), 2.19-2.35 (m, 6H), 2.44-2.53 (m, 2H), 3.41 (s, 3H), 3.55-3.77(m, 2H), 4.41-4.75 (m, 4H), 6.77-6.93 (m, 2H), 7.02-7.13 (m, 2H), 7.28(d, J=8.1 Hz, 2H), 7.37-7.47 (m, J=8.1 Hz, 2H), 12.13-12.46 (m, 1H).

Example 57(4)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.44 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.64-1.38 (m, 13H), 1.44-2.14 (m, 10H), 2.11-2.27 (m,1H), 2.32 (s, 2H), 2.40-2.66 (m, 6H), 3.56 (s, 2H), 3.97 (d, J=7.5 Hz,2H), 4.36-4.89 (m, 4H), 6.47-7.00 (m, 1H), 6.96-7.20 (m, 3H), 7.30-7.57(m, 4H).

Example 57(5)N-(1H-imidazol-2-ylmethyl)-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.39 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 0.97 (d, J=6.2 Hz, 6H), 1.37-1.90(m, 7H), 2.02 (d, J=7.1 Hz, 2H), 2.05-2.10 (m, 1H), 2.16-2.44 (m, 6H),2.53 (t, J=6.9 Hz, 2H), 3.56 (s, 2H), 3.98 (d, J=7.3 Hz, 2H), 4.33-4.93(m, 4H), 6.79-6.95 (m, 1H), 6.97-7.18 (m, 3H), 7.28-7.56 (m, 4H).

Example 57(6)4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.40 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.87 (t, J=7.4 Hz, 6H), 0.97 (d, J=6.4 Hz, 6H), 1.16-1.68(m, 7H), 1.79-1.93 (m, 4H), 1.97-2.15 (m, 1H), 2.32 (s, 2H), 2.33-2.45(m, 4H), 2.52 (t, J=6.9 Hz, 2H), 3.56 (s, 2H), 3.97 (d, J=7.0 Hz, 2H),4.29-5.00 (m, 4H), 6.73-6.97 (m, 1H), 6.98-7.19 (m, 3H), 7.28-7.59 (m,4H).

Example 57(7)4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide

TLC: Rf 0.45 (chloroform:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.84 (s, 9H), 0.97 (d, J=6.4 Hz, 6H), 1.40-1.85 (m, 6H),1.88-2.15 (m, 3H), 2.22-2.46 (m, 6H), 2.47-2.65 (m, 2H), 3.56 (s, 2H),3.97 (d, J=7.1 Hz, 2H), 4.40-4.93 (m, 4H), 6.80-6.96 (m, 1H), 6.96-7.17(m, 3H), 7.29-7.52 (m, 4H).

Example 581-(1-methyl-1H-imidazol-2-yl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

The same operation as in Example 2→Example 3 was performed, except forusing 1-methyl-1H-imidazole-2-carbaldehyde in place of2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide in Example 2, to obtainthe title compound having the following physical properties.

TLC: Rf 0.63 (chloroform:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 3.63 (s, 6H), 3.87 (s, 4H), 6.82 (s, 2H), 6.93 (s, 2H).

Example 594-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]benzamide

The same operation as in Example 4→Example 8 was performed, except forusing the amine obtained in Example 58 in place of2,2′-[iminobis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)in Example 4, to obtain the title compound having the following physicalproperties.

TLC: Rf 0.53 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.83 (s, 9H), 1.46-1.67 (m, 6H), 1.97 (s, 2H), 2.31 (s,2H), 2.29-2.46 (m, 4H), 2.52 (t, J=6.9 Hz, 2H), 3.34-3.53 (m, 3H), 3.55(s, 2H), 3.65-3.90 (m, 3H), 4.54-4.93 (m, 4H), 6.73-6.83 (m, 2H),6.87-7.07 (m, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H).

Example 601-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

The same operation as in Example 4→Example 8 was performed, except forusing 8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decane in place of2,2′-[iminobis(methylene)]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)in Example 4, and the amine obtained in Example 58 in place oftrans-4-piperidin-1-ylcyclohexaneamine in Example 8, to obtain the titlecompound having the following physical properties.

TLC: Rf 0.30 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.80-0.96 (m, 6H), 1.18-1.84 (m, 10H), 2.14 (m, 1H),2.24-2.60 (m, 4H), 3.16-3.75 (m, 16H), 6.78-6.82 (m, 2H), 6.90-6.93 (m,2H), 7.22-7.30 (m, 2H), 7.43 (d, J=7.8 Hz, 2H).

Example 60(1) to Example 60(3)

The same operation was carried out, except for using a correspondingamine in place of 8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decane in Example60, to obtain the following compound.

Example 60(1)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.31 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.80-0.89 (m, 9H), 1.40-1.83 (m, 6H), 1.96-2.07 (m, 2H),2.22-2.60 (m, 4H), 3.18-3.73 (m, 16H), 6.80 (s, 2H), 6.93 (s, 2H),7.21-7.30 (m, 2H), 7.40-7.46 (m, 2H).

Example 60(2)1-(4-{[9-(2,2-dimethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.34 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.72-0.90 (m, 9H), 1.55-1.85 (m, 4H), 1.95-2.10 (m, 2H),2.28-2.62 (m, 4H), 3.12-3.80 (m, 18H), 6.79-6.81 (m, 2H), 6.92-6.94 (m,2H), 7.27-7.34 (m, 4H).

Example 60(3)1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine

TLC: Rf 0.34 (dichrolomethane:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.77-0.95 (m, 6H), 1.12-1.85 (m, 8H), 2.10 (m, 1H),2.22-2.63 (m, 4H), 3.10-3.83 (m, 18H), 6.78-6.81 (m, 2H), 6.92-6.94 (m,2H), 7.24-7.34 (m, 4H).

Example 61 Ethyl{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}(oxo)acetate

4-(tert-butoxycarbonylamino)piperidine (150 mg) was added toacetonitrile (5 mL), and triethylamine (0.21 mL) and ethyloxalylchloride (0.11 mL) were added dropwise at 0° C. The reaction solutionwas stirred for 30 minutes and an aqueous saturated sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate.The organic layer was washed in turn with water and saturated brine,dried over anhydrous magnesium sulfate and then concentrated underreduced pressure to obtain the title compound (235 mg) having thefollowing physical properties.

TLC: Rf 0.48 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.37 (t, J=6.00 Hz, 3H), 1.37-1.50 (m, 2H), 1.44 (s, 9H),1.96-2.08 (m, 2H), 2.80-2.93 (m, 1H), 3.10-3.23 (m, 1H), 3.59-3.75 (m,2H), 4.26-4.44 (m, 3H), 4.58 (d, J=7.32 Hz, 1H).

Example 62 {4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}(oxo)aceticacid

To an ethanol (3 mL) solution of the compound (235 mg) obtained inExample 61, 2N-sodium hydroxide water (0.75 mL) was added. The reactionsolution was stirred for 15 hours, and then concentrated by adding 2Nhydrochloric acid to obtain the title compound (240 mg) having thefollowing physical properties.

TLC: Rf 0.20 (chloroform:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CD₃OD): δ 1.28-1.53 (m, 2H), 1.43 (s, 9H), 1.86-1.98 (m, 2H),2.87-3.00 (m, 1H), 3.18-3.29 (m, 1H), 3.56-3.68 (m, 1H), 3.68-3.82 (m,1H), 4.18-4.37 (m, 1H).

Example 63 Tert-butyl{1-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)(oxo)acetyl]piperidin-4-yl}carbamate

The compound (240 mg) obtained in Example 62,8-(2-methylpropyl)-2,8-diazaspiro[4.5]decane (133 mg),N,N,N′,N′-tetramethyl-ortho-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (518 mg) and diisopropyl ethylamine (0.24 mL) wereadded to dimethylformamide (5 mL), followed by stirring for 2 hours. Tothe reaction solution, saturated brine was added, followed by extractionwith dichloromethane. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (ethylacetate:methanol=9:1→ethyl acetate:methanol:28% aqueousammonia=29:1:0.2→8:1:0.2) to obtain the title compound (236 mg) havingthe following physical properties.

TLC: Rf 0.78 (ethyl acetate:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 0.90 (d, J=6.59 Hz, 6H), 1.32-1.87 (m, 9H), 1.44 (s, 9H),1.93-2.18 (m, 4H), 2.24-2.39 (m, 2H), 2.40-2.60 (m, 2H), 2.78-2.94 (m,1H), 3.07-3.19 (m, 1H), 3.21-3.33 (m, 1H), 3.36 (s, 1H), 3.55 (t, J=7.41Hz, 2H), 3.64-3.77 (m, 2H), 4.36-4.47 (m, 1H), 4.48-4.60 (m, 1H).

Example 641-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)(oxo)acetyl]piperidine-4-amine

Except for using the compound (236 mg) produced in Example 63, the sameoperation as in Example 25 was performed to obtain the title compound(144 mg) having the following physical properties.

TLC: Rf 0.29 (dichrolomethane:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.81 (d, J=6.59, 6H), 1.12-1.91 (m, 11H), 1.99 (d, J=9.00Hz, 2H), 2.08-2.46 (m, 4H), 2.70-2.90 (m, 1H), 2.97-3.12 (m, 1H),3.17-3.23 (m, 1H), 3.25-3.32 (m, 1H), 3.42-3.55 (m, 2H), 3.53-3.76 (m,2H), 4.23-4.42 (m, 1H).

Example 65N,N-bis(1H-imidazol-2-ylmethyl)-1-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)(oxo)acetyl]-4-piperidinamine

The same operation as in Example 2 was performed, except for using thecompound (144 mg) obtained in Example 64 in place of benzylamine, and1H-imidazole-2-carbaldehyde (158 mg) in place of the compound obtainedin Example 1, to obtain the title compound having the following physicalproperties.

TLC: Rf 0.42 (dichrolomethane:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 0.84-0.94 (m, 6H), 1.32-2.00 (m, 11H), 2.02-2.11 (m, 2H),2.17-2.32 (m, 2H), 2.35-2.53 (m, 2H), 2.59-2.85 (m, 2H), 2.95-3.10 (m,1H), 3.15-3.91 (m, 9H), 4.42-4.56 (m, 1H), 7.03 (s, 4H).

Example 65(1) to Example 65(9)

Except for using the corresponding amine in place of4-(tert-butoxycarbonylamino)piperidine in Example 61 and using thecorresponding amine in place of8-(2-methylpropyl)-2,8-diazaspiro[4.5]decane in Example 61, the sameoperation as in Example 61→Example 62→Example 63→Example 64→Example 65was performed to obtain the following compound.

Example 65(1)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-({1-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)(oxo)acetyl]-4-piperidinyl}methyl)methanamine

TLC: Rf 0.40 (dichrolomethane:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 0.84-0.91 (m, 6H), 0.97-1.21 (m, 2H), 1.46-1.97 (m, 10H),2.02-2.11 (m, 2H), 2.17-2.52 (m, 6H), 2.60-2.78 (m, 1H), 2.97-3.11 (m,1H), 3.17-3.38 (m, 2H), 3.41-3.71 (m, 7H), 4.39-4.53 (m, 1H), 7.04 (s,4H).

Example 65(2)1-[3-(8-benzyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine

TLC: Rf 0.43 (dichrolomethane:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 1.21-1.98 (m, 10H), 2.20-2.40 (m, 2H), 2.42-2.64 (m, 3H),2.69-2.82 (m, 1H), 2.96-3.13 (m, 1H), 3.24-3.63 (m, 8H), 3.66-3.83 (m,4H), 3.83-3.97 (m, 1H), 4.48-4.61 (m, 1H), 7.01 (s, 4H), 7.20-7.37 (m,5H).

Example 65(3)1-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-N,N-bis(1H-imidazol-2-ylmethyl)-3-pyrrolidinamine

TLC: Rf 0.50 (dichrolomethane:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.84-1.92 (m, 16H), 1.97-2.21 (m, 2H), 2.22-2.36 (m, 1H),2.36-2.52 (m, 2H), 2.55-2.68 (m, 2H), 3.09-4.02 (m, 15H), 7.03 (d, J=1.2Hz, 4H).

Example 65(4)1-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine

TLC: Rf 0.42 (dichrolomethane:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.96-2.02 (m, 20H), 2.19-2.81 (m, 7H), 2.96-3.12 (m, 1H),3.22-3.93 (m, 11H), 4.46-4.62 (m, 1H), 7.06 (s, 4H).

Example 65(5)1-{3-[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-oxopropanoyl}-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine

TLC: Rf 0.33 (dichrolomethane:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 0.83-0.95 (m, 6H), 1.19-1.99 (m, 14H), 2.09-2.22 (m, 1H),2.32-2.64 (m, 5H), 2.66-2.80 (m, 1H), 2.97-3.11 (m, 1H), 3.22-3.66 (m,6H), 3.67-3.82 (m, 4H), 3.82-3.94 (m, 1H), 4.49-4.61 (m, 1H), 7.01 (s,4H).

Example 65(6)1-{3-[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-oxopropanoyl}-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 0.84 (s, 9H), 1.19-1.98 (m, 10H), 1.99-2.06 (m, 2H),2.30-2.65 (m, 5H), 2.65-2.83 (m, 1H), 2.96-3.12 (m, 1H), 3.22-3.64 (m,6H), 3.65-3.82 (m, 4H), 3.81-3.94 (m, 1H), 4.45-4.62 (m, 1H), 7.01 (s,4H).

Example 65(7)N,N-bis(1H-imidazol-2-ylmethyl)-1-[3-(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-4-piperidinamine

TLC: Rf 0.70 (dichrolomethane:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.88 (d, J=6.6 Hz, 6H), 1.21-1.98 (m, 11H), 2.00-2.11 (m,2H), 2.15-2.35 (m, 2H), 2.35-2.49 (m, 2H), 2.49-2.63 (m, 1H), 2.65-2.80(m, 1H), 2.97-3.10 (m, 1H), 3.23-3.65 (m, 6H), 3.66-3.81 (m, 4H),3.81-3.91 (m, 1H), 4.49-4.60 (m, 1H), 7.00 (s, 4H).

Example 65(8)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-({1-[3-(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropanoyl]-4-piperidinyl}methyl)methanamine

TLC: Rf 0.41 (dichrolomethane:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 0.88 (d, J=6.6 Hz, 6H), 1.02-1.95 (m, 12H), 2.01-2.10 (m,2H), 2.13-2.51 (m, 6H), 2.52-2.67 (m, 1H), 2.98-3.16 (m, 1H), 3.24-3.57(m, 6H), 3.60 (s, 4H), 3.80-3.93 (m, 1H), 4.48-4.62 (m, 1H), 7.03 (s,4H).

Example 65(9)1-[4-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-4-oxobutanoyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine

TLC: Rf 0.46 (dichrolomethane:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 0.79-1.95 (m, 20H), 2.18-3.07 (m, 12H), 3.21-3.67 (m,4H), 3.70-3.84 (m, 4H), 3.86-4.00 (m, 1H), 4.47-4.61 (m, 1H), 7.01 (s,4H).

Example 66 Methyl {4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}acetate

4-(tert-butoxycarbonylamino)piperidine (1.2 g) and potassium carbonate(1.2 g) were suspended in dimethylformamide (20 mL), and then methylbromoacetate (0.62 mL) was added. The reaction solution was stirred forone hour and water was added, followed by extraction with ethyl acetate.The organic layer was washed in turn with water and saturated brine, anddried over anhydrous magnesium sulfate, and then the filtrate wasconcentrated. The residue was purified by silica gel chromatography(hexane:ethyl acetate=2:10:1) to obtain the title compound (1.36 g)having the following physical properties.

TLC: Rf 0.79 (ethyl acetate:methanol:28% aqueous ammonia=8:1:0.2);

NMR (CDCl₃): δ 1.44 (s, 9H), 1.46-1.61 (m, 2H), 1.87-2.00 (m, 2H),2.19-2.34 (m, 2H), 2.83-2.94 (m, 2H), 3.21 (s, 2H), 3.39-3.56 (m, 1H),3.72 (s, 3H), 4.60 (d, J=6.77 Hz, 1H).

Example 67 {4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}acetic acid

Except for using the compound produced in Example 66 in place of thecompound produced in Example 61, the same operation as in Example 62 wasperformed to obtain the title compound having the following physicalproperties.

TLC: Rf 0.10 (chloroform:methanol:28% aqueous ammonia=4:1:0.2);

NMR (DMSO-d₆): δ 1.37 (s, 9H), 1.47-1.63 (m, 2H), 1.73-1.85 (m, 2H),2.61-2.73 (m, 2H), 3.07-3.21 (m, 2H), 3.28 (s, 2H), 3.29-3.43 (m, 1H),6.91 (d, J=7.14 Hz, 1H).

Example 68 Tert-butyl{1-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]piperidin-4-yl}carbamate

Except for using the compound produced in Example 67 in place of thecompound produced in Example 62 and using8-cyclohexyl-2,8-diazaspiro[4.5]decane in place of8-(2-methylpropyl)-2,8-diazaspiro[4.5]decane, the same operation as inExample 63 was performed to obtain the title compound having thefollowing physical properties.

TLC: Rf 0.60 (ethyl acetate:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.97-1.98 (m, 20H), 1.44 (s, 9H), 2.12-2.34 (m, 3H),2.36-2.68 (m, 4H), 2.83-2.94 (m, 2H), 3.05-3.12 (m, 2H), 3.28-3.35 (m,2H), 3.41-3.59 (m, 3H), 4.40-4.53 (m, 1H).

Example 691-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]piperidine-4-amine

Except for using the compound produced in Example 68 in place of thecompound produced in Example 63, the same operation as in Example 64 wasperformed to obtain the title compound having the following physicalproperties.

TLC: Rf 0.29 (chloroform:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.96-1.94 (m, 20H), 2.16 (t, J=11.44 Hz, 2H), 2.23-2.36(m, 1H), 2.37-2.73 (m, 5H), 2.82-2.91 (m, 2H), 3.08 (s, 1H), 3.10 (s,1H), 3.32 (s, 1H), 3.36 (s, 1H), 3.50 (t, J=7.32 Hz, 1H), 3.57 (t,J=7.05 Hz, 1H).

Example 701-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine

Except for using the compound (30 mg) produced in Example 69 in place ofthe compound produced in Example 64, the same operation as in Example 65was performed to obtain the title compound having the following physicalproperties.

TLC: Rf 0.80 (dichrolomethane:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.98-1.94 (m, 20H), 1.98-2.11 (m, 2H), 2.21-2.36 (m, 1H),2.37-2.69 (m, 5H), 2.90-3.03 (m, 2H), 3.06 (s, 1H), 3.07 (s, 1H), 3.31(s, 2H), 3.45-3.60 (m, 2H), 3.77 (s, 4H), 7.00 (s, 4H).

Example 70(1) to Example 70(2)

Except for using the corresponding amine in place of4-(tert-butoxycarbonylamino)piperidine and using corresponding bromidein place of methyl bromoacetate, the same operation as in Example 61 wasperformed to obtain the compound of the present invention having thefollowing physical properties.

Example 70(1)1-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-3-oxopropyl]-N,N-bis(1H-imidazol-2-ylmethyl)-4-piperidinamine

TLC: Rf 0.69 (dichrolomethane:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.97-2.10 (m, 22H), 2.22-2.74 (m, 10H), 2.87-2.98 (m,2H), 3.25 (s, 1H), 3.30 (s, 1H), 3.43-3.55 (m, 2H), 3.76 (s, 2H), 3.80(s, 2H), 7.00 (s, 2H), 7.01 (s, 2H).

Example 70(2)1-{1-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]-4-piperidinyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine

TLC: Rf 0.38 (dichrolomethane:methanol:28% aqueous ammonia=4:1:0.2);

NMR (CDCl₃): δ 0.97-1.91 (m, 21H), 1.94-2.10 (m, 2H), 2.19-2.68 (m, 5H),2.34 (d, J=7.1 Hz, 2H), 2.82-2.96 (m, 2H), 3.07 (s, 1H), 3.08 (s, 1H),3.32 (s, 1H), 3.37 (s, 1H), 3.45-3.68 (m, 2H), 3.60 (s, 4H), 7.03 (s,4H).,

BIOLOGICAL EXAMPLES

Efficacy of the compound of the present invention, for example the factthat the compound of the present invention has CXCR4 antagonisticactivity, has been demonstrated by the following experiment.

A measuring method of the present invention was modified to improveaccuracy and/or sensitivity of the measurement for evaluating thecompound of the present invention. The detailed experimental methods areshown bellow.

As mentioned above, a more direct procedure is a screening a compoundthat prevents for HIV from binding to CXCR4, which is a receptor on CD4+cell, on an assay system using HIV viruses. However, using HIV virusesfor a large-scale screening is not practical due to its difficulthandling. On the other hand, both of T cell-directed (X4) HIV-1 andSDF-1 bind to CXCR4 and therefore CXCR4 binding sites at both ofHIV-side and SDF-1-side as well as SDF-1- and HIV-binding sites at theCXCR4 side may presumably have any common characteristics. Thus, to finda compound inhibiting absorption of HIV viruses to a cell that is adifferent mechanism from those of pre-existing anti-AIDS drugs (reversetranscriptase inhibitors and protease inhibitors), an assay system usingan endogenous ligand for CXCR4, SDF-1 instead of HIV may be available.

Specifically, as a system of screening a compound that inhibits thebinding between SDF-1 and CXCR4, for example a system of measuring thebinding between iodine-labeled SDF-1 and a human T cell strain in whichCXCR4 is known to be expressed is operable. The identical idea ispossible since macrophage (R5) HIV and RANTES, MIP-1α, and MIP-1β allbind to CCR5.

Test Methods Test Example 1 Study for Inhibition of Binding Human SDF-1to CEM Cells

To human T cell strain CEM cells in a binding buffer (containing HEPESand BSA), the test compound and ¹²⁵I-SDF-1 (NEN) were added and themixture was incubated at 4° C. for 60 minutes. The reacted CEM cellswere rapidly filtrated with a GF/B membrane filter plate (Packard) toadsorb. The plate was washed with PBS three times and then dried.Microscint+20 (Packard) was added thereto. An amount of theradioactivity bound to the CEM cells was measured using Top Count(Packard) and inhibition (%) of the test compound was calculatedaccording to the following equation:Inhibition={(Et−Ea)/(Et−Ec)}×100

wherein

Et: amount of radioactivity when the test compound is not added,

Ec: amount of radioactivity when non-radioactive SDF-1 (Pepro Tech) isadded in an amount of 1000 times as much as ¹²⁵I-SDF-1 as a testcompound, and

Ea: amount of radioactivity when the test compound is added.

All compounds of the present invention shown in the Example exhibitedinhibition of 50% or more in a concentration of 10 μM. For example, IC₅₀value for compound 8(113) was 15 nM.

Test Example 2 Measurement of the Influence of a Compound of the PresentInvention on Blood Pressure and Heart Rate

A rat is anesthetized with urethane (1.2 g/kg subcutaneousadministration). After neck midline dissection, a catheter for measuringblood pressure is inserted into a right common carotid artery. Then,after dissecting inguinal region, a catheter for chemical injection isinserted into a femoral vein and fixed. A catheter for measurement ofblood pressure is connected to a pressure transducer and then thepressure waveform is recorded on a thermal writing pen recorder throughan amplifier for strain compression (AP-641G (manufactured by NIHONKOHDEN CORPORATION)). In this case, regarding a heart rate, a valuethrough a cardiotachometer (AT-601G (manufactured by NIHON KOHDENCORPORATION)) using the pressure waveform obtained from the amplifierfor strain compression as a trigger is recorded on a thermal writing penrecorder. The test compound is dissolved in a 10% solubilizingagent/physiological saline solution (volume ratio of polyoxyethylenehydroxystearate:propylene glycol:physiological saline=7:3:190) so as toadjust the concentration to 0.1, 0.3, 1, 3 or 10 mg/mL to preparesolutions. Each solution is intravenous administered at 1 mL/Kg throughthe caudal vein over about 10 seconds. Accumulative administration ofstepwise increasing in dosage is carried out to an individual.

Test Example 3 Measurement of Maximum Plasma Level (CMax) andBioavailability (BA)

A test compound is weighed, dissolved in Solutol (trade name;manufactured by BASF-TAKEDA Vitamins Ltd.)/propylene glycol=7/3 which isheated to 60° C. and adjusted to 20 mg/mL; thereafter, the test compoundis diluted by 10 times with distilled water for injection, and furtherdiluted by 2 times with saline solution, by which intravenouslyadministered solution is eventually made. The test compound is weighed,dissolved in Solutol (trade name; manufactured by BASF-TAKEDA VitaminsLtd.)/propylene glycol=7/3 which is heated to 60° C., and adjusted to 20mg/mL; thereafter, the test compound is diluted by 10 times withdistilled water for injection, by which orally administered solution iseventually made. Intravenous administration is performed by rapid singleadministration (n=3) of intravenously administered solution (1 mg/kg)from the tail vein of Crl:CD(SD) Rat (male, manufactured by CHARLESRIVER LABORATORIES JAPAN, INC). Oral administration is performed byforced administration (n=3) of orally administered solution (10 mg/kg)into the stomach of Crl:CD(SD) Rat (male, manufactured by CHARLES RIVERLABORATORIES JAPAN, INC.) using a sonde. The administration is conductedunder fasting conditions; water is freely ingested. A 0.35 mL bloodsample is taken from cervical vein by using Heparinized Syringe at 15minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24hours after administration. The obtained blood is stored in ice, andafter centrifugation at 12,000 rpm for 5 minutes, blood plasma isfractionated. The blood plasma is preserved at a temperature of −80° C.The sample of blood plasma preserved at a temperature of −80° C. isdissolved; inner standard solution (100 μL) and acetonitrile (2 mL) areadded to the blood plasma sample 100 μL and stirred; and the sample iscentrifuged at 2,500 rpm for 10 minutes. After the supernatant isevaporated to dryness by means of a centrifugal concentrator, 67%dimethyl sulfoxide solution (150 μL) is added to the residue anddissolves them again; and 20 μL of the solution is analyzed by means ofLC/MS/MS.

The analysis by means of LC/MS/MS should be performed, for example,under the following conditions:

[LC Conditions]

Measurement device: Waters 2795 (manufactured by Waters Corporation)

Analytical column: Unison UK-C18, 3.0 μm particle size, 2.0 mm×30 mm(manufactured by Imtakt Corporation)

Analytical column temperature: Room temperature

Flow rate: 200 μL/min

Moving bed: 5 mM IPC-PFAA-7 solution/acetonitrile (9/1→1/9)

[MS/MS Conditions]

Measurement device: Quatro micro API (manufactured by MicromassCommunications Inc.)

Method for ionization: ES+

Capillary electric potential: 3.30 kV

Source temperature: 120° C.

Desolvation temperature: 350° C.

Multiplier: 650 V

The monitor ion which was suitable for each sample was selected.

The concentration transition in the rat blood plasma of the testcompound is analyzed by means of non-compartment analysis method byusing WinNonlin 4.0.1 (manufactured by Pharsight Corporation) tocalculate the maximum blood concentration Cmax and the area under theblood concentration curve AUC.

BA is calculated by means of the following formula:BA(%)={(AUC_(p.o.)/Dose_(p.o.))/(AUC_(i.v.)/Dose_(i.v.))}×100

AUC_(p.o.): AUC in oral administration

Dose_(p.o.): Amount of the drug orally administered

AUC_(i.v.): AUC in intravenous administration

Dose_(i.v.): Amount of the drug intravenously administered

The maximum blood concentration Cmax of the compound of the presentinvention indicated good values. For example, the maximum bloodconcentrations Cmax of Example 8 (113), Example 40 (68), Example 40 (72)and Example 65 (4) were as shown in Table 1.

Cmax Compound (ng/mL) Example 8 (113) 80 Example 8 (114) 46 Example 40(68) 175 Example 40 (72) 157 Example 65 (4) 420

Test Example 4 Investigation with a Phospholipidosis Detecting SystemUsing Fluorescent Labeling Phospholipidosis Analog

(i) Phospholipid Accumulation Measurement

100 μL/well as required (1 dose 2 wells) of cell suspension of CHL/IU(cell line derived from a Chinese hamster lung) adjusted by MEM (7×10⁴cells/mL) adjusted by MEM (minimum essential medium) culture medium wasadded to a 96-well plate (96-well clear-bottom plate), and cultured forabout 24 hours. After culture, the supernatant of the 96-well plate wasremoved, and the 100 μL/well compounds of each concentration dissolvedand suspended in a minimum essential medium (MEM) including 25 μmol/Lnitrobenzoxadiazole dipalmitoyl phosphatidylethanolamine (NBD-PE)(hereinafter abbreviated as a NPD-PE medium) were added and treated forabout 24 hours. The treatment concentrations of each compound were setto be 6.25, 12.5, 25, 50 and 100 μmol/L. The positive control substancewas set to be amiodarone hydrochloride, and the treatment concentrationswere set to be 1.25, 2.5, 5, 10 and 20 μmol/L. In addition, 5 untreatedcontrols (only MEM) and 5 NBD-PE controls (made by means of adding a1/100 amount of DMSO to the NBD-PE culture medium) were set percompound, and cultured in the same manner. After finishing the culture,the cultures were washed twice with Phosphate buffered saline(hereinafter abbreviated as PBS) (−) 100 μL/well, and the MEM (100 μL)was added to all of the treatment wells including 2 empty wells forWST-1 background controls and cultured for about a half hour. Thefluorescence intensities of each well were measured by using amicroplate reader (manufactured by Molecular Devices Inc., SPECTRA maxM2; the excitation wavelength 485 nm/the fluorescence wavelength 535nm).

(ii) Analysis

Using the average values of each dose×2 wells, a phospholipid increaserate (%) to the NBD-PE control was calculated by using the followingcalculating formula:Phospholipid increase rate (%)=100×{(test article fluorescenceintensity−untreated control fluorescence intensity)/(NBD-PE controlfluorescence intensity−untreated control fluorescence intensity(iii) Cytotoxicity Assay

The 96-well plate measured in the phospholipid accumulation measurementwas measured by means of Plate Reader (manufactured by Molecular DevicesInc., SPECTRA max M2) with the main wavelength of 450 nm and the correctwavelength of 690 nm to calculate a Pre value. An amount of 5 μL/well ofPremix WS T-1 was added to each of the 96 hole plates by which Premeasurement was conducted. After culture for 2 to 4 hours, the 96-wellplate was measured as well as the Pre measurement to calculate an Aftvalue. Then, the background control value was subtracted from the eachmeasured value. A value which was calculated by subtracting the Prevalue from the Aft value was used, then the cell growth rate (%) wascalculated by using the following calculating formula:Cell growth rate (%)=100×{(test article OD)/(NBD-PE control OD)}(iv) Determination

A test dose that indicated value of equal to or more than 25% of themaximum phospholipid accumulation increase rate of amiodarone which wasthe positive control was determined as positive. In addition, the dosewhose cell growth rate was equal to or less than 50% in the cytotoxicityassay was not used for determination of existence or nonexistence of aphospholipidosis inductive effect.

As a result, it was found that the compound of the present invention hada low phospholipidosis inductive effect in vitro experiment system.

The rate of increase of phopholipid accumulation (%) Compound (compounddose: 50 μM) Judgement Example 8 (113) 10 negative Example 40 (68) 18negative Example 40 (72) 16 negative Example 65 (4) 12 negative

Test Example 5 Artificial Lipid Membrane Binding Account by UsingBiacore (Registered Trademark) S51 System

(i) Liposome Adjustment

10 mM of 1,2-Dioleoyl-sn-Glycero-3-Phosphate, Monosodium Salt(hereinafter abbreviated as DOPA) chloroform solution was evaporated todryness by means of an aspirator, and 0.6 mL of PBS/5% dimethylsulfoxide (hereinafter abbreviated as DMSO) was added. The chloroformsolution was fully suspended by means of a vortex mixer, and thefreezing and thawing were repeated for 5 times. Liposome was created bymeans of a liposome adjustment instrument (manufactured by Avestin Inc.)and 2 syringes, and was diluted to 0.5 mM with PBS/5% DMSO just prior toimmobilization.

(ii) Measurement Compound Adjustment

The 38 μL of 1×PBS is added to 2 μL DMSO solution (10 mM), and furtherthe 360 μL 1×PBS/5% DMSO was added; the 50 μM of final concentration inthe 1×PBS/5% DMSO was adjusted and measured.

(iii) Analysis

All of the following analysis used Biacore® S51 system; the measurementconditions were set by Biacore S51 Control Soft.

The measurement temperature was set to be 37° C., and the 1×PBS/5% DMSO(pH 7.4 or PH 6.0) was used as a buffer. Series S Sensor Chip L1 wasused for a sensor chip. The DOPA was immobilized in one of the measuringspots on the sensor surface, and the central spot was used as areference.

Immobilization of liposome was conducted at a flow rate of 10 μL/min forabout 3 minutes; then the compound was added at a flow rate of 30 μL/minand the interaction was measured. The measurement conditions are asfollows:

Assay buffer: PBS/5% DMSO (pH 7.4 or PH 6.0)

Measurement temperature: 37° C.

Sensor chip: Series S Sensor Chip L1

Flow rate: 10 μL/min at the time of the liposome immobilization; 30μL/min at the time of the measurement of interaction with the compound

Regeneration: 20 mM CHAPS(3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate),Isopropanol/50 mM sodium hydroxide solution=40/60 (volume ratio) mixture(60 seconds)

(iv) Data Processing

The data processing was conducted by means of method of Abdiche et al.(Analytical biochemistry, 328, 233-243 (2004)) by using Biacore S51Evaluation Soft.

Regarding the value of binding response (RU) in which the value ofreference was subtracted, it was divided by a sample molecular weightafter minute error of the DMSO concentration included in the samplesolution was corrected. In addition, the value obtained here was dividedby an amount of capture at the time of the cycle because the valueobtained here was proportional to the amount of capture of the liposome;further, the value was multiplied by a million to be considered as acorrected value (Corrected value=1000000)×RU (test compound)/molecularquantity (test compound) RU (liposome)).

Propranolol, Amiodarone, Desipramine, Imipramine and Procaine were addedas the controls, and it was recognized that the variation of the bindingresponse was within ca. 10 to 15%.

(v) Determination

The compound, in which a value of the binding response after thecorrection was equal to or more than 150, was determined as positive.

As a result, it was found that the compound of the present invention hada low phospholipidosis inductive effect in vitro experiment system.

Corrected value of Compound binding response (RU) Judgement Example 8(113) 66.6 negative Example 8 (114) 80.7 negative Example 40 (68) 77.6negative Example 40 (72) 72.0 negative Example 65 (4) 36.0 negative

Formulation Examples Formulation Example 1

N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,8-diazaspiro[4.5]dec-8-yl)methyl]benzamide(200 g), calcium carboxymethyl cellulose (disintegrant, 20.0 g),magnesium stearate (lubricants, 10.0 g) and microcrystalline cellulose(870 g) were mixed by a conventional method and then compressed toobtain 10,000 tablets each containing 20 mg of an active ingredient.

Formulation Example 2

N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,8-diazaspiro[4.5]dec-8-yl)methyl]benzamide(100 g), mannitol (2 kg) and distilled water (50 L) were mixed by aconventional method and filtered with a dust filter, and then eachampoule was filled with 5 mL of the obtained mixture and subjected toheat sterilization in an autoclave to obtain 10,000 ampoules eachcontaining 10 mg of an active ingredient.

INDUSTRIAL APPLICABILITY

The compound of the present invention has CXCR4 antagonistic activityand is therefore useful as a preventive and/or therapeutic agent forCXCR4-mediated diseases. Accordingly, the compound of the presentinvention can be available as a drug. For example, the compound of thepresent invention is useful as a preventive and/or therapeutic agent forinflammatory and immune diseases (for example, rheumatoid arthritis,arthritis, systemic lupus erythematosus, retinopathy, maculardegeneration, pulmonary fibrosis, transplanted organ rejection, etc.),allergic diseases, infections (for example, human immunodeficiency virusinfection, acquired immunodeficiency syndrome, etc.), cancerous diseases(for example, cancer, cancer metastasis, etc.), cardiac or vasculardisease (for example, arteriosclerosis, myocardial infarction,stenocardia, cerebral infarction, chronic occlusive disease, etc.),psychoneurotic diseases, cerebral diseases, and metabolic diseases, oran agent for regeneration therapy. In addition, the compound of thepresent invention is therefore useful as a preventive and/or therapeuticagent for cancerous diseases or infections.

The invention claimed is:
 1. A compound represented by formula (I):

wherein A¹ and A² each independently represents a group having a basicgroup; B¹ and B² each independently represents a bond or a spacer havinga main chain of 1 to 4 atom(s); E represents a spacer having a mainchain of 1 to 10 atom(s); L represents a bond or a spacer having a mainchain of 1 to 4 atom(s); J represents (1) an aliphatic hydrocarbon groupwhich is substituted with a group having a basic group, and also mayhave a substituent(s), (2) a monocyclic or condensed cyclic group whichis substituted with a group having a basic group, and also may have asubstituent(s), (3) a spiro-bound cyclic group which may be substitutedwith a group having a basic group, and also may have a substituent(s),or (4) a bridged cyclic group which may be substituted with a grouphaving a basic group, and also may have a substituent(s); G represents abond, a carbon atom which may have a substituent(s), an oxygen atom, anitrogen atom which may have a substituent(s), an optionally oxidizedsulfur atom, or -carbon atom which may have a substituent(s)-nitrogenatom which may have a substituent(s)-; wherein when J represents (1) or(2), G represents a bond, a carbonyl group, an oxygen atom, a nitrogenatom which may have a substituent(s) or an optionally oxidized sulfuratom, or B¹ represents a spacer having a main chain of 1 to 4 atom(s)composed of 1 to 4 group(s) selected optionally from —O—, —S—, —CO—,—SO—, —SO₂— and a divalent nitrogen atom which may have a substituent(s)wherein the compound of formula (I) is chosen from (1)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)-2,6-dimethylbenzamide,(2)3-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(3)4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(4)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(4-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(5)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(4-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}methyl)benzamide,(6)4-{[8-(3-hydroxypropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(7)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)-3-methoxybenzamide,(8)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(8-{[3-(methoxymethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,(9)4-({8-[(3-chloro-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(10)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(2-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(11)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(3-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(12)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(4-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(13)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(2-methoxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(14)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(3-methoxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(15)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(4-methoxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(16)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-(trifluoromethyl)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(17)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[3-(trifluoromethyl)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(18)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[4-(trifluoromethyl)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(19)2,6-dichloro-N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(20)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(8-{[3-(trifluoromethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,(21)4-[(8-{[3-(hydroxymethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(22)2-{[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-3-thiophenecarboxylicacid, (23)2-{[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]carbonyl}benzyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-3-thiophenecarboxamide,(24)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(3-methoxy-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(25)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(2-nitrobenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(26)4-{[8-(2-cyanobenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(27)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-(trifluoromethoxy)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(28)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-(methylthio)benzyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(29)4-{[8-(2-hydroxybenzyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(30)4-({8-[(3-fluoro-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(31)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(5-nitro-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(32)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzamide,(33)N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-1H-imidazole-2-carboxamide,(34)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzamide,(35)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzamide,(36)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzamide,(37)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzamide,(38)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzamide,(39)N,N-bis(1H-imidazol-2-ylmethyl)-4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzamide,(40)4-[(8-{[3-(1-hydroxyethyl)-2-thienyl]methyl}-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(41)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[(3-methyl-2-thienyl)carbonyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(42)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzamide,(43)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]methyl}benzamide,(44)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}methyl)benzamide,(45)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[2-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}benzamide,(46)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}methyl)benzamide,(47)N,N-bis(1H-imidazol-2-ylmethyl)-4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[4.4]non-2-yl}methyl)benzamide,(48)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)benzamide,(49)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[7-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}benzamide,(50)N,N-bis(1H-imidazol-2-ylmethyl)-4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-2-yl}methyl)benzamide,(51)4-{[8-(2-hydroxy-2-methylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(52)4-{[8-(3-hydroxy-3-methylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(53)4-{[8-(4-hydroxy-4-methylpentyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(54)4-{[8-(2-ethyl-2-hydroxybutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(55)4-({8-[(1-hydroxycyclohexyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(56)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[8-(1-propylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}benzamide,(57)4-({8-[2-hydroxy-1-(hydroxymethyl)ethyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(58)4-{[8-(2-hydroxy-2-propylpentyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(59)N,N-bis(1H-imidazol-2-ylmethyl)-4-({8-[2-methoxy-1-(methoxymethyl)ethyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzamide,(60)4-{[9-(2-ethylbutyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(61)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]benzamide,(62)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(tetrahydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzamide,(63)4-[(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(64)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-2,9-diazaspiro[5.5]undec-2-yl)methyl]benzamide,(65)4-{[9-(cyclobutylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(66)4-({9-[(3-chloro-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(67)3-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(68)4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)methyl]-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(69)4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(70)4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(71)N-(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(72)N-(1H-imidazol-2-ylmethyl)-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(73)N-(1H-imidazol-2-ylmethyl)-4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(74)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(7-isobutyl-2,7-diazaspiro[3.5]non-2-yl)methyl]benzamide,(75)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,7-diazaspiro[3.5]non-7-yl)methyl]benzamide,(76)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,8-diazaspiro[4.5]dec-8-yl)methyl]benzamide,(77)4-{[2-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(78)4-{[2-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(79)4-{[9-(1-ethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(80)4-{[9-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(81)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(4-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)methyl]benzamide,(82)4-{[4-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(83)4-{[2-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(84)4-{[2-(1-ethylpropyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(85)4-{[7-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(86)4-{[7-(1-ethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(87)N,N-bis(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,9-diazaspiro[5.5]undec-9-yl)methyl]benzamide,(88)4-{[2-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(89)4-{[2-(1-ethylpropyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(90)4-{[9-(2,2-dimethylpropyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(91)4-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(92)4-({8-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-N,N-bis(1H-imidazol-2-ylmethyl)benzamide,(93)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzenesulfonamide,(94)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzenesulfonamide,(95)N,N-bis(1H-imidazol-2-ylmethyl)-4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzenesulfonamide,(96)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzenesulfonamide,(97)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzenesulfonamide,(98)N,N-bis(1H-imidazol-2-ylmethyl)-4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzenesulfonamide,(99)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzenesulfonamide

, (100)N,N-bis(1H-imidazol-2-ylmethyl)-4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)benzenesulfonamide,(101)N,N-bis(1H-imidazol-2-ylmethyl)-4-{[7-(2-thienylmethyl)-2,7-diazaspiro[4.4]non-2-yl]methyl}benzenesulfonamide,(102)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]methanamine,(103)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[7-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-2-yl]methyl}benzyl)methanamine,(104)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-2-yl}methyl)benzyl]methanamine,(105)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,7-diazaspiro[3.5]non-7-yl]methyl}benzyl)methanamine,(106)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}methyl)benzyl]methanamine,(107)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzyl]methanamine,(108)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzyl)methanamine,(109)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]methanamine,(110)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzyl)methanamine,(111)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzyl]methanamine,(112)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]methanamine,(113)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]methyl}benzyl)methanamine,(114)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}methyl)benzyl]methanamine,(115)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]methyl}benzyl)methanamine,(116)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}methyl)benzyl]methanamine,(117)1-{4-[(1′-cyclohexylspiro[indole-3,4′-piperidin]-1(2H)-yl)methyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(118)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-phenyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}methanamine,(119)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}benzyl)methanamine,(120)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(121) methyl5-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}-2-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzoate,(122)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-[(1-ethyl-1H-imidazol-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)methanamine,(123)1-[4-({8-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(124)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isopropyl-1H-imidazol-2-yl)methyl]methanamine,(125)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine,(126)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(127)1-{3-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(128)2-(2-{[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)amino]methyl}-1H-imidazol-1-yl)ethanol,(129)[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-cyclohexyl-2,8-diazaspiro[4.5]dec-3-yl]methanol,(130)1-{4-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)ethyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(131)2-(2-{[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(1H-imidazol-2-ylmethyl)amino]methyl}-1H-imidazol-1-yl)-N,N-dimethylacetamide,(132)N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-8-yl}methyl)benzyl]-1H-imidazole-2-carboxamide,(133)N-(1H-imidazol-2-ylmethyl)-N-(4-{[2-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}benzyl)-1H-imidazole-2-carboxamide,(134)N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]-1H-imidazole-2-carboxamide,(135)N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]methyl}benzyl)-1H-imidazole-2-carboxamide,(136)N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}methyl)benzyl]-1H-imidazole-2-carboxamide,(137)N-(1H-imidazol-2-ylmethyl)-N-[4-({4-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}methyl)benzyl]-1H-imidazole-2-carboxamide,(138)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-(1H-imidazol-2-ylmethyl)-1H-imidazole-2-carboxamide,(139)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}methanamine,(140)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}carbonyl)benzyl]methanamine,(141)1-(4-{[8-(2-ethylbutyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(142)1-{4-[(8-cyclopentyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(143)1-(4-{[8-(cyclohexylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(144)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[8-(2-methylbenzyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}benzyl)methanamine,(145)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(146)1-{4-[(9-cyclohexyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(147)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-thienylmethyl)-3,9-diazaspiro[5.5]undec-3-yl]carbonyl}benzyl)methanamine,(148)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-3,9-diazaspiro[5.5]undec-3-yl}carbonyl)benzyl]methanamine,(149)1-{4-[(8-cycloheptyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(150)1-(4-{[8-(cyclopentylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(151)1-(4-{[8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(152)1-{4-[(2-cyclohexyl-2,7-diazaspiro[3.5]non-7-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(153)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({7-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-2-yl}carbonyl)benzyl]methanamine,(154)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({2-[(3-methyl-2-thienyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}carbonyl)benzyl]methanamine,(155)1-{4-[(7-cyclohexyl-2,7-diazaspiro[3.5]non-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(156)1-{4-[(9-cyclohexyl-2,9-diazaspiro[5.5]undec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(157)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}carbonyl)benzyl]methanamine,(158)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(7-isobutyl-2,7-diazaspiro[3.5]non-2-yl)carbonyl]benzyl}methanamine,(159)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(2-isobutyl-2,7-diazaspiro[3.5]non-7-yl)carbonyl]benzyl}methanamine,(160)1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(161)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-isopropyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}methanamine,(162)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(9-isobutyl-2,9-diazaspiro[5.5]undec-2-yl)carbonyl]benzyl}methanamine,(163)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methyl-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}carbonyl)benzyl]methanamine,(164)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]benzyl}methanamine,(165)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]benzyl}methanamine,(166)1-{4-[(9-cyclohexyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(167)1-(1H-imidazol-2-yl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(168)1-(1H-imidazol-2-yl)-N-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]benzyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(169)1-(1H-imidazol-2-yl)-N-{4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]benzyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(170)1-{4-[(9-cyclopentyl-2,9-diazaspiro[5.5]undec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(171)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(tetrahydro-2H-pyran-4-yl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine,(172)1-[4-({8-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}carbonyl)phenyl]-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(173)1-(4-{[9-(2-ethylbutyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(174)1-(4-{[9-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(175)1-(4-{[9-(cyclohexylmethyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(176)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(2-methylbenzyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine,(177)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methoxy-2-thienyl)methyl]-2,9-diazaspiro[5.5]undec-2-yl}carbonyl)benzyl]methanamine,(178)1-(4-{[9-(1-ethylpropyl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(179)1-{4-[(9-cycloheptyl-2,9-diazaspiro[5,5]undec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(180)(2-{[2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoyl)-2,9-diazaspiro[5.5]undec-9-yl]methyl}-3-thienyl)methanol,(181)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine,(182)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(tetrahydro-2H-thiopyran-4-yl)-2,9-diazaspiro[5.5]undec-2-yl]carbonyl}benzyl)methanamine,(183)1-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(184)1-{4-[(9-isobutyl-3,9-diazaspiro[5.5]undec-3-yl)carbonyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(185)1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(186)1-(4-{[9-(2,2-dimethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(187)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({9-[(3-methoxy-2-thienyl)methyl]-1-oxa-4,9-diazaspiro[5.5]undec-4-yl}carbonyl)benzyl]methanamine,(188)(2-{[4-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzoyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl]methyl}-3-thienyl)methanol,(189)1-{4-[(9-cycloheptyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(190)1-{4-[(9-cyclopentyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(191)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-(4-{[9-(tetrahydro-2H-pyran-4-yl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}benzyl)methanamine,(192)1-(4-{[9-(cyclohexylmethyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(193)1-{4-[(9-isobutyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)carbonyl]phenyl}-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(194)1-{4-[2-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(195) 1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[2-(8isobutyl-2,8-diazaspiro[4.5]dec-2-yl)-2-oxoethyl]benzyl}methanamine,(196)1-(4-{[7-(1-ethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(197)1-(4-{[7-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-2-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(198)1-(4-{[2-(2,2-dimethylpropyl)-2,7-diazaspiro[3.5]non-7-yl]carbonyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(199)1-(4-{[9-(1-ethylpropyl)-3,9-diazaspiro[5.5]undec-3-yl]carbonyl}-phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(200)1-{3-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(201)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{3-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}methanamine,(202)1-(4-{[9-(2,2-dimethylpropyl)-3,9-diazaspiro[5.5]undec-3-yl]carbonyl}-phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(203)1-(4-{2-[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-2-oxoethyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(204) 1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[2 (8isobutyl-2,8-diazaspiro[4.5]dec-2-yl)-1,1-dimethyl-2-oxoethyl]benzyl}methanamine,(205) 1(4-{2-[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]-2-oxoethyl}phenyl)-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(206)1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}-phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(207)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(208)1-(4-{[9-(2,2-dimethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(209)1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(210)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]phenyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine,(211)1-(1H-imidazol-2-yl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine,(212)1-(4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine,(213)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]methanamine,(214)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)sulfonyl]benzyl}methanamine,(215)1-(1H-imidazol-2-yl)-N-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}sulfonyl)benzyl]methanamine,(216)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)sulfonyl]phenyl}-N,N-bis(1H-imidazol-2-ylmethyl)methanamine,(217)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-cyclohexyl-2,8-diazaspiro[4.5]decan-3-one,(218)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decan-3-one,(219)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]decan-3-one,(220)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decan-3-one,(221)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-cyclohexyl-2,8-diazaspiro[4.5]decan-1-one,(222)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-isobutyl-2,8-diazaspiro[4.5]decan-1-one,(223)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]decan-1-one,(224)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-8-(1-ethylpropyl)-2,8-diazaspiro[4.5]decan-1-one,(225)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-cyclohexyl-2,9-diazaspiro[5.5]undecan-1-one,(226)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-isobutyl-2,9-diazaspiro[5.5]undecan-1-one,(227)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-(2,2-dimethylpropyl)-2,9-diazaspiro[5.5]undecan-1-one,(228)2-(4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzyl)-9-(1-ethylpropyl)-2,9-diazaspiro[5.5]undecan-1-one(229)N-(1H-imidazol-2-ylmethyl)-4-[(2-isobutyl-2,8-diazaspiro[4.5]dec-8-yl)methyl]-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(230)4-{[2-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(231)4-{[2-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzamide,(232)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide,(233)N-(1H-imidazol-2-ylmethyl)-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide,(234)4-{[8-(1-ethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide,(235)4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}-N-(1H-imidazol-2-ylmethyl)-N-[(1-isobutyl-1H-imidazol-2-yl)methyl]benzamide,(236)1-(4-{[8-(2,2-dimethylpropyl)-2,8-diazaspiro[4.5]dec-2-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(237)1-(4-{[9-(2,2-dimethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,(238)1-(4-{[9-(1-ethylpropyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl]carbonyl}phenyl)-N,N-bis[(1-methyl-1H-imidazol-2-yl)methyl]methanamine,a salt thereof, or an N-oxide thereof.
 2. A pharmaceutical compositioncomprising the compound according to claim 1, a salt thereof, or anN-oxide thereof.
 3. A pharmaceutical composition comprising the compoundaccording to claim 1, a salt thereof, an N-oxide thereof, and one ormore kinds selected from reverse transcriptase inhibitor, proteaseinhibitor, CCR2 antagonist, CCR3 antagonist, CCR4 antagonist, CCR5antagonist, CXCR4 antagonist, HIV integrase inhibitor, fusion inhibitor,CD4 antagonist, antibody against surface antigen of HIV, ShortInterfering RNA targeting a HIV-related factor, and vaccine of HIV.